Contingent cardio-protection for epilepsy patients

ABSTRACT

Disclosed are methods and systems for treating epilepsy by stimulating a main trunk of a vagus nerve, or a left vagus nerve, when the patient has had no seizure or a seizure that is not characterized by cardiac changes such as an increase in heart rate, and stimulating a cardiac branch of a vagus nerve, or a right vagus nerve, when the patient has had a seizure characterized by cardiac changes such as a heart rate increase.

CROSS-REFERENCE TO RELATED APPLICATIONS

This presently being filed application is a continuation-in-part of andclaims priority to co-pending U.S. patent application Ser. No.16/690,452 entitled “Contingent Cardio-Protection For EpilepsyPatients”, filed on Nov. 21, 2019 which is a continuation-in-part of andclaims priority to U.S. patent application Ser. No. 15/437,155 entitled“Contingent Cardio-Protection For Epilepsy Patients”, filed on Feb. 20,2017 (Now U.S. Pat. No. 10,682,515), U.S. patent application Ser. No.15/437,155 claims priority to and is a divisional application of U.S.patent application Ser. No. 14/050,173 entitled “ContingentCardio-Protection For Epilepsy Patients”, filed on Oct. 9, 2013 (nowU.S. Pat. No. 9,579,506), which claims priority to and is acontinuation-in-part of U.S. patent application Ser. No. 13/601,099entitled “Contingent Cardio-Protection For Epilepsy Patients”, filed onAug. 31, 2012 (now U.S. Pat. No. 9,314,633) all of which areincorporated herein by reference in their entireties.

BACKGROUND OF THE DISCLOSURE

This disclosure relates generally to medical devices, and, moreparticularly, to methods, apparatus, and systems for performing vagusnerve stimulation (VNS) for treating epileptic seizures characterized bycardiac changes, including ictal tachycardia.

DESCRIPTION OF THE RELATED ART

While seizures are the best known and most studied manifestation ofepilepsy, cardiac alterations are prevalent and may account for the highrate of sudden unexpected death (SUDEP) in these patients. Thesealterations may include changes in rate (most commonly tachycardia,rarely bradycardia or asystole), rhythm (PACs, PVCs), conduction (e.g.,bundle branch block) and repolarization abnormalities (e.g., Q-Tprolongation, which occurs primarily during (ictal) but also betweenseizures (inter-ictally). In addition, S-T segment depression (a sign ofmyocardial ischemia) is observed during epileptic seizures. Significantelevations in heart-type fatty acid binding protein (H-FABP), acytoplasmic low-molecular weight protein released into the circulationduring myocardial injury have been documented in patients with epilepsyand without evidence of coronary artery disease, not only duringseizures but also during free-seizure periods. H-FABP is a moresensitive and specific marker of myocardial ischemia than troponin I orCK-MB. Elevations in H-FABP appear to be un-correlated with duration ofillness, of the recorded seizures, or with the Chalfont severity scoreof the patients.

The cardiac alterations in epilepsy patients, both during and betweenseizures, have a multi-factorial etiology, but a vago-sympatheticimbalance seems to play a prominent role in their generation. Themajority of epileptic seizures enhance the sympathetic tone (plasmanoradrenaline and adrenaline rise markedly after seizure onset) causingtachycardia, arterial hypertension and increases in the respiratoryrate, among others. Recurrent and frequent exposure to the outpouring ofcatecholamines associated with seizures in patients withpharmaco-resistant epilepsies may, for example, account forabnormalities that increase the risk of sudden death such asprolongation of the Q-T interval which leads to often fataltachyarrhythmias such as torsade de pointe. Further evidence in supportof the role of catecholamines in SUDEP is found in autopsies of SUDEPvictims, revealing interstitial myocardial fibrosis (a risk factor forlethal arrhythmias), myocyte vacuolization, atrophy of cardiomyocytes,leukocytic infiltration, and perivascular fibrosis. Restoration of thesympathetic-parasympathetic tone to normal levels, a therapeuticobjective that may be accomplished by enhancing parasympathetic activitythrough among others, electrical stimulation of the vagus nerve, maydecrease the rate and severity of cardiac and autonomic co-morbiditiesin these patients.

While there have been significant advances over the last several decadesin treatments for epileptic seizures, the management ofco-morbidities—in particular the cardiac alterations associated withseizures—remains largely unaddressed. There is a need for improvedepilepsy treatments that address cardiac impairments associated withseizures. Pharmacological therapies for neurological diseases (includingepilepsy) have been available for many decades. A more recent treatmentfor neurological disorders involves electrical stimulation of a targettissue to reduce symptoms or effects of the disorder. Such therapeuticelectrical signals have been successfully applied to brain, spinal cord,and cranial nerves tissues improve or ameliorate a variety ofconditions. A particular example of such a therapy involves applying anelectrical signal to the vagus nerve to reduce or eliminate epilepticseizures, as described in U.S. Pat. Nos. 4,702,254, 4,867,164, and5,025,807, which are hereby incorporated herein by reference in theirentirety.

The endogenous electrical activity (i.e., activity attributable to thenatural functioning of the patient's own body) of a neural structure maybe modulated in a variety of ways. One such way is by applying exogenous(i.e., from a source other than the patient's own body) electrical,chemical, or mechanical signals to the neural structure. In someembodiments, the exogenous signal (“neurostimulation” or“neuromodulation”) may involve the induction of afferent actionpotentials, efferent action potentials, or both, in the neuralstructure. In some embodiments, the exogenous (therapeutic) signal mayblock or interrupt the transmission of endogenous (natural) electricalactivity in the target neural structure. Electrical signal therapy maybe provided by implanting an electrical device underneath the skin of apatient and delivering an electrical signal to a nerve such as a cranialnerve.

In one embodiment, the electrical signal therapy may involve detecting asymptom or event associated with the patient's medical condition, andthe electrical signal may be delivered in response to the detection.This type of stimulation is generally referred to as “closed-loop,”“active,” “feedback,” “contingent” or “triggered” stimulation.Alternatively, the system may operate according to a predeterminedprogram to periodically apply a series of electrical pulses to the nerveintermittently throughout the day, or over another predetermined timeinterval. This type of stimulation is generally referred to as“open-loop,” “passive,” “non-feedback,” “non-contingent” or“prophylactic,” stimulation.

In other embodiments, both open- and closed-loop stimulation modes maybe used. For example, an open-loop electrical signal may operate as a“default” program that is repeated according to a programmed on-time andoff-time until a condition is detected by one or more body sensorsand/or algorithms. The open-loop electrical signal may then beinterrupted in response to the detection, and the closed-loop electricalsignal may be applied—either for a predetermined time or until thedetected condition has been effectively treated. The closed-loop signalmay then be interrupted, and the open-loop program may be resumed.Therapeutic electrical stimulation may be applied by an implantablemedical device (IMD) within the patient's body or, in some embodiments,externally.

Closed-loop stimulation of the vagus nerve has been proposed to treatepileptic seizures. Many patients with intractable, refractory seizuresexperience changes in heart rate and/or other autonomic body signalsnear the clinical onset of seizures. In some instances the changes mayoccur prior to the clinical onset, and in other cases the changes mayoccur at or after the clinical onset. Where the changes involves heartrate, most often the rate increases, although in some instances a dropor a biphasic change (up-then-down or down-then-up) may occur. It ispossible using a heart rate sensor to detect such changes and toinitiate therapeutic electrical stimulation (e.g., VNS) based on thedetected change. The closed-loop therapy may be a modified version of anopen-loop therapy. See, e.g., U.S. Pat. Nos. 5,928,272, and 6,341,236,each hereby incorporated by reference herein. The detected change mayalso be used to warn a patient or third party of an impending oroccurring seizure.

VNS therapy for epilepsy patients typically involves a train ofelectrical pulses applied to the nerve with an electrode pair includinga cathode and an anode located on a left or right main vagal trunk inthe neck (cervical) area. Only the cathode is capable of generatingaction potentials in nerve fibers within the vagus nerve; the anode mayblock some or all of the action potentials that reach it (whetherendogenous or exogenously generated by the cathode). VNS as an epilepsytherapy involves modulation of one or more brain structures. Therefore,to prevent the anode from blocking action potentials generated by thecathode from reaching the brain, the cathode is usually located proximalto the brain relative to the anode. For vagal stimulation in the neckarea, the cathode is thus usually the upper electrode and the anode isthe lower electrode. This arrangement is believed to result in partialblockage of action potentials distal to or below the anode (i.e., thosethat would travel through the vagus nerve branches innervating thelungs, heart and other viscerae). Using an upper-cathode/lower-anodearrangement has also been favored to minimize any effect of the vagusnerve stimulation on the heart.

Stimulation of the left vagus nerve, for treatment of epilepsy hascomplex effects on heart rate (see Frei & Osorio, Epilepsia 2001), oneof which includes slowing of the heart rate, while stimulation of theright vagus nerve has a more prominent bradycardic effect. Electricalstimulation of the right vagus nerve has been proposed for use in theoperating room to slow the heart during heart bypass surgery, to providea surgeon with a longer time period to place sutures between heartbeats(see, e.g., U.S. Pat. No. 5,651,373). Some patents discussing VNStherapy for epilepsy treatment express concern with the risk ofinadvertently slowing the heart during stimulation. In U.S. Pat. No.4,702,254, it is suggested that by locating the VNS stimulationelectrodes below the inferior cardiac nerve, “minimal slowing of theheart rate is achieved” (col. 7 lines 3-5), and in U.S. Pat. No.6,920,357, the use of a pacemaker to avoid inadvertent slowing of theheart is disclosed.

Cranial nerve stimulation has also been suggested for disorders outsidethe brain such as those affecting the gastrointestinal system, thepancreas (e.g., diabetes, which often features impaired production ofinsulin by the islets of Langerhans in the pancreas), or the kidneys.Electrical signal stimulation of either the brain alone or the organalone may have some efficacy in treating such medical conditions, butmay lack maximal efficacy.

While electrical stimulation has been used for many years to treat anumber of conditions, a need exists for improved VNS methods of treatingepilepsy and its cardiac co-morbidities as well as other brain andnon-brain disorders.

SUMMARY OF THE DISCLOSURE

In one aspect, the present disclosure relates to a method of treating apatient having epilepsy comprising receiving at least one body datastream, analyzing the at least one body data stream using a seizure orevent detection algorithm to detect whether or not the patient is havingand/or has had an epileptic seizure, receiving a cardiac signal of thepatient, applying a first electrical signal to a vagus nerve of thepatient based on a determination that the patient is not having and/orhas not had an epileptic seizure characterized by a decrease in thepatient's heart rate, wherein the first electrical signal is not a vagusnerve conduction blocking electrical signal, and applying a secondelectrical signal to a vagus nerve of the patient based on adetermination that the patient is having and/or has had an epilepticseizure characterized by a decrease in the patient's heart rate, whereinthe second electrical signal is a pulsed electrical signal that blocksaction potential conduction in the vagus nerve.

In one aspect, the present disclosure relates to a method of treating apatient having epilepsy comprising sensing a cardiac signal and akinetic signal of the patient, analyzing at least one of the cardiacsignal and the kinetic signal; determining whether or not the patienthas had an epileptic seizure based on the analyzing; in response to adetermination that the patient has had an epileptic seizure, determiningwhether or not the seizure is characterized by a decrease in thepatient's heart rate, applying a first electrical signal to a vagusnerve of the patient based on a determination that the patient has hadan epileptic seizure characterized by a decrease in the patient's heartrate, wherein the first electrical signal is a pulsed electrical signalthat blocks action potential conduction in the vagus nerve; and applyinga second electrical signal to a vagus nerve of the patient based on oneof a) a determination that the patient has not had an epileptic seizure,and b) a determination that the patient has had an epileptic seizurethat is not characterized by a decrease in the patient's heart rate,wherein the second electrical signal is not a vagus nerve conductionblocking electrical signal.

In one aspect, the present disclosure relates to a system for treating amedical condition in a patient, comprising at least one electrodecoupled to a vagus nerve of the patient, a programmable electricalsignal generator, a sensor for sensing at least one body data stream, aseizure detection module capable of analyzing the at least one body datastream and determining, based on the analyzing, whether or not thepatient is having and/or has had an epileptic seizure, a heart ratedetermination unit capable of determining a heart rate of a patientproximate in time to an epileptic seizure detected by the seizuredetection module, and a logic unit for applying a first electricalsignal to the vagus nerve using the at least one electrode based on adetermination by the seizure detection module that the patient is havingand/or has had an epileptic seizure characterized by a decrease in thepatient's heart rate, wherein the first electrical signal is a pulsedelectrical signal that blocks action potential conduction in the vagusnerve, and for applying a second electrical signal to the vagus nerveusing the at least one electrode as a cathode based upon one of a) adetermination that the patient is not having and/or has not had anepileptic seizure, and b) a determination that the patient is havingand/or has had an epileptic seizure that is not characterized by adecrease in the patient's heart rate, wherein the second electricalsignal is not a vagus nerve conduction blocking electrical signal. Inone embodiment, the seizure detection module may comprise the heart ratedetermination unit.

In one aspect, the present disclosure relates to a method of treating apatient having epilepsy comprising applying a first electrical signal toa vagus nerve of the patient, wherein the first electrical signal is anopen-loop electrical signal having a programmed on-time and a programmedoff-time, sensing at least one body signal of the patient, determiningthe start of an epileptic seizure based on the at least one body signal,determining whether or not the seizure is characterized by a decrease inthe patient's heart rate, applying a second, closed-loop electricalsignal to a vagus nerve of the patient based on a determination that theepileptic seizure is not characterized by a decrease in the patient'sheart rate, and applying a third, closed-loop electrical signal to avagus nerve of the patient based on a determination that the seizure ischaracterized by a decrease in the patient's heart rate, wherein thethird electrical signal is applied to block action potential conductionon the vagus nerve.

In one aspect, the present disclosure relates to a method of controllinga heart rate of an epilepsy patient comprising sensing a kinetic signalof the patient; analyzing said kinetic signal to determine at least onekinetic index; receiving a cardiac signal of the patient; analyzing thecardiac signal to determine the patient's heart rate; determining if thepatient's heart rate is commensurate with the at least one kineticindex; and applying a first electrical signal to a vagus nerve of thepatient based on a determination that the patient's heart rate is notcommensurate with the kinetic index. In one embodiment, the at least onekinetic index comprises at least one of an activity level or an activitytype of the patient, and determining if the heart rate is commensuratewith the kinetic index comprises determining if the heart rate iscommensurate with the at least one of an activity level or an activitytype.

In one aspect, the present disclosure relates to a method of controllinga heart rate of an epilepsy patient comprising sensing at least one of akinetic signal and a metabolic (e.g., oxygen consumption) signal of thepatient; receiving a cardiac signal of the patient; analyzing thecardiac signal to determine the patient's heart rate; determining if thepatient's heart rate is commensurate with the at least one of a kineticand a metabolic signal of the patient; and applying a first electricalsignal to a vagus nerve of the patient based on a determination that thepatient's heart rate is not commensurate with the at least one of akinetic signal and a metabolic signal. In one embodiment, the methodfurther comprises determining at least one of an activity level or anactivity type of the patient based on the at least one of a kinetic anda metabolic signal, and determining if the heart rate is commensuratewith the kinetic signal comprises determining if the heart rate iscommensurate with the at least one of an activity level or an activitytype.

In one aspect, the present disclosure relates to a method of treating apatient having epilepsy comprising sensing at least one body signal ofthe patient; determining whether or not the patient is having or has hadan epileptic seizure based on the at least one body signal; sensing acardiac signal of the patient; determining whether or not the seizure isassociated with a change in the patient's cardiac signal; applying afirst therapy to a vagus nerve of the patient based on a determinationthat the patient is having or has had an epileptic seizure that is notassociated with a change in the patient's cardiac signal, wherein thefirst therapy is selected from an electrical, chemical, mechanical(e.g., pressure) or thermal signal. The method further comprisesapplying a second therapy to a vagus nerve of the patient based on adetermination that the patient has had an epileptic seizure associatedwith a change in the patient's cardiac signal, wherein the secondtherapy is selected from an electrical, chemical, mechanical (e.g.,pressure) or thermal signal. In some embodiments, a third therapy may beapplied to a vagus nerve based a determination that the patient has nothad an epileptic seizure, wherein the third therapy is selected form anelectrical, chemical, mechanical or thermal signal.

BRIEF DESCRIPTION OF THE DRAWINGS

The disclosure may be understood by reference to the followingdescription taken in conjunction with the accompanying drawings, inwhich like reference numerals identify like elements, and in which:

FIGS. 1A-1E provide stylized diagrams of an implantable medical deviceimplanted into a patient's body for providing first and secondelectrical signals to a vagus nerve of a patient for treating epilepticseizures, in accordance with one illustrative embodiment of the presentdisclosure;

FIG. 2 illustrates a block diagram depiction of an implantable medicaldevice of FIG. 1, in accordance with one illustrative embodiment of thepresent disclosure;

FIG. 3 illustrates a block diagram depiction of an electrode polarityreversal unit shown in FIG. 2, in accordance with one illustrativeembodiment of the present disclosure;

FIG. 4 illustrates a flowchart depiction of a method for providing firstand second electrical signals to a main trunk and a cardiac branch of avagus nerve, respectively, based upon whether or not the patient ishaving and/or has had an epileptic seizure, in accordance with anillustrative embodiment of the present disclosure;

FIG. 5 illustrates a flowchart depiction of a method for providing firstand second electrical signals to a main trunk and a cardiac branch of avagus nerve, respectively, based upon whether or not at least one of acardiac signal and a kinetic signal indicates that the patient is havingand/or has had an epileptic seizure, and whether the seizure ischaracterized by an increase in heart rate, in accordance with anillustrative embodiment of the present disclosure;

FIG. 6 illustrates a flowchart depiction of a method for providing afirst, open-loop electrical signal to a main trunk of a vagus nerve, asecond, closed-loop electrical signal to the main trunk of the vagusnerve based upon the patient having had an epileptic seizure notcharacterized by an increase in heart rate, and a third, closed-loopelectrical signal to a cardiac branch of a vagus nerve based upon thepatient having had an epileptic seizure characterized by an increase inheart rate, in accordance with an illustrative embodiment of the presentdisclosure; and

FIG. 7 is a flowchart depiction of a method for providing closed-loopvagus nerve stimulation for a patient with epilepsy by stimulating aright vagus nerve in response to detecting a seizure with tachycardiaand stimulating a left vagus nerve in the absence of such a detection.For example if a recumbent person's heart rate is 55 bpm and itincreases to 85 during a seizure, this is not clinical/pathologicaltachycardia, but may be considered tachycardia within the meaning ofsome embodiments of the present disclosure.

FIG. 8 is a flowchart depiction of a method for providing a closed-looptherapy to a vagus nerve of a patient with epilepsy in response todetecting a seizure associated with a heart rate decrease, wherein saidtherapy blocks impulse conduction along at least one vagus nerve.

FIG. 9 is a flowchart depicting a method for providing closed-loop vagusnerve stimulation based on an assessment of whether the patient's heartrate is commensurate with the patient's activity level or activity type.

FIG. 10 is a flowchart depicting a method for providing closed-loopvagus nerve stimulation based on a determination that the patient'sheart rate is incommensurate with the patient's activity level oractivity type, and further in view of whether the incommensurate changesinvolves relative tachycardia or relative bradycardia.

FIG. 11 is a graph of heart rate versus time, according to oneembodiment.

FIG. 12 is another graph of heart rate versus time, according to oneembodiment.

FIG. 13 is another graph of heart rate versus time, according to oneembodiment.

FIG. 14 is another graph of heart rate versus time, according to oneembodiment.

FIG. 15 is another graph of heart rate versus time, according to oneembodiment.

FIG. 16 is a flowchart of a therapy procedure, according to oneembodiment.

FIG. 17 is a graph relating to the automated detection and control ofictal and peri-ictal chronotropic instability, according to oneembodiment.

FIG. 18 is a graph relating to the automated detection and control ofictal and peri-ictal chronotropic instability, according to oneembodiment.

FIG. 19 is a graph relating to the automated detection and control ofictal and peri-ictal chronotropic instability, according to oneembodiment.

FIG. 20 is a graph relating to the automated detection and control ofictal and peri-ictal chronotropic instability, according to oneembodiment.

FIG. 21 is a graph relating to the automated detection and control ofictal and peri-ictal chronotropic instability, according to oneembodiment.

FIG. 22A provides a stylized diagram of an implantable medical deviceimplanted into a patient's body for providing a therapeutic electricalsignal to a neural structure of the patient's body, in accordance withone illustrative embodiment of the present disclosure;

FIG. 22B provides a stylized diagram of a medical device systemcomprising an implantable medical device implanted into a patient's bodyfor providing a therapeutic electrical signal to a neural structure ofthe patient's body, and an external device for administering aresponsiveness test to a patient, in accordance with anotherillustrative embodiment of the present disclosure;

FIG. 23A is a block diagram of a medical device system that includes amedical device, in accordance with one illustrative embodiment of thepresent disclosure;

FIG. 23B is a block diagram of a medical device system that includes amedical device and a responsiveness test unit, in accordance with oneillustrative embodiment of the present disclosure;

FIG. 24A is a block diagram of a medical device system that includes amedical device, in accordance with one illustrative embodiment of thepresent disclosure;

FIG. 24B is a block diagram of a medical device system that includes amedical device and a responsiveness test unit, in accordance with oneillustrative embodiment of the present disclosure;

FIG. 25A is a block diagram of a medical device system that includes amedical device, in accordance with one illustrative embodiment of thepresent disclosure;

FIG. 25B is a block diagram of a medical device system that includes amedical device and a responsiveness test unit, in accordance with oneillustrative embodiment of the present disclosure;

FIG. 26 illustrates a block diagram of a change in autonomic orneurologic index detection unit of the medical device system, inaccordance with one illustrative embodiment of the present disclosure;

FIG. 27A illustrates a flowchart depiction of determining aresponsiveness of a patient, in accordance with one illustrativeembodiment of the present disclosure;

FIG. 27B illustrates a flowchart depiction of determining aresponsiveness of a patient in combination with the delivery and/ormodification of therapy, in accordance with one illustrative embodimentof the present disclosure;

FIG. 27C illustrates a flowchart depiction of determining aresponsiveness of a patient in combination with an override based on anautonomic or neurologic index value, in accordance with one illustrativeembodiment of the present disclosure;

FIG. 27D depicts one particular embodiment of administering a test ofthe patient's responsiveness, in accordance with one illustrativeembodiment of the present disclosure; and

FIG. 27E depicts one particular embodiment of administering a test ofthe patient's responsiveness, in accordance with one illustrativeembodiment of the present disclosure.

While the disclosure is susceptible to various modifications andalternative forms, specific embodiments thereof have been shown by wayof example in the drawings and are herein described in detail. It shouldbe understood, however, that the description herein of specificembodiments is not intended to limit the disclosure to the particularforms disclosed, but on the contrary, the intention is to cover allmodifications, equivalents, and alternatives falling within the spiritand scope of the disclosure as defined by the appended claims.

DETAILED DESCRIPTION OF SPECIFIC EMBODIMENTS

Illustrative embodiments of the disclosure are described herein. Forclarity, not all features of an actual implementation are provided indetail. In any actual embodiment, numerous implementation-specificdecisions must be made to achieve the design-specific goals. Such adevelopment effort, while possibly complex and time-consuming, wouldnevertheless be a routine task for persons of skill in the art giventhis disclosure.

This application does not intend to distinguish between components thatdiffer in name but not function. “Including” and “includes” are used inan open-ended fashion, and should be interpreted to mean “including, butnot limited to.” “Couple” or “couples” are intended to mean either adirect or an indirect electrical connection. “Direct contact,” “directattachment,” or providing a “direct coupling” indicates that a surfaceof a first element contacts the surface of a second element with nosubstantial attenuating medium there between. Small quantities ofsubstances, such as bodily fluids, that do not substantially attenuateelectrical connections do not vitiate direct contact. “Or” is used inthe inclusive sense (i.e., “and/or”) unless a specific use to thecontrary is explicitly stated.

“Electrode” or “electrodes” may refer to one or more stimulationelectrodes (i.e., electrodes for applying an electrical signal generatedby an IMD to a tissue), sensing electrodes (i.e., electrodes for sensinga body signal), and/or electrodes capable of either stimulation orsensing. “Cathode” and “anode” have their standard meanings, as theelectrode at which current leaves the IMD system and the electrode atwhich current enters the IMD system, respectively. Reversing thepolarity of the electrodes can be effected by any switching techniqueknown in the art.

A “pulse” is used herein to refer to a single application of electricalcharge from the cathode to target neural tissue. A pulse may includeboth a therapeutic portion (in which most or all of the therapeutic oraction-potential-generating effect occurs) and a charge-balancingportion in which the polarity of the electrodes are reversed and theelectrical current is allowed to flow in the opposite direction to avoidelectrode and/or tissue damage. Individual pulses are separated by atime period in which no charge is delivered to the nerve, which can becalled the “interpulse interval.” A “burst” is used herein to refer to aplurality of pulses, which may be separated from other bursts by aninterburst interval in which no charge is delivered to the nerve. Theinterburst intervals have a duration exceeding the interpulse intervalduration. In one embodiment, the interburst interval is at least twiceas long as the interpulse interval. The time period between the end ofthe last pulse of a first burst and the initiation of the first pulse ofthe next subsequent burst can be called the “interburst interval.” Inone embodiment, the interburst interval is at least 100 msec.

A plurality of pulses can refer to any of (a) a number of consecutivepulses within a burst, (b) all the pulses of a burst, or (c) a number ofconsecutive pulses including the final pulse of a first burst and thefirst pulse of the next subsequent burst.

“Stimulate,” “stimulating” and “stimulator” may generally refer toapplying a signal, stimulus, or impulse to neural tissue (e.g., a volumeof neural tissue in the brain or a nerve) for affecting it neuronalactivity. While the effect of such stimulation on neuronal activity istermed “modulation,” for simplicity, the terms “stimulating” and“modulating”, and variants thereof, are sometimes used interchangeablyherein. The modulation effect of a stimulation signal on neural tissuemay be excitatory or inhibitory, and may potentiate acute and/orlong-term changes in neuronal activity. For example, the modulationeffect of a stimulation signal may comprise: (a) initiating actionpotentials in the target neural tissue; (b) inhibition of conduction ofaction potentials (whether endogenous or exogenously generated, orblocking their conduction (e.g., by hyperpolarizing or collisionblocking), (c) changes in neurotransmitter/neuromodulator release oruptake, and (d) changes in neuroplasticity or neurogenesis of braintissue. Applying an electrical signal to an autonomic nerve may comprisegenerating a response that includes an afferent action potential, anefferent action potential, an afferent hyperpolarization, an efferenthyperpolarization, an afferent sub-threshold depolarization, and/or anefferent sub-threshold depolarization. The terms tachycardia andbradycardia are used here in a relative (i.e., any decrease or decreasein heart rate relative to a reference value) or in an absolute sense(i.e., a pathological change relative to a normative value). Inparticular, “tachycardia is used interchangeably with an increase heartrate and “bradycardia” may be used interchangeably with a decrease inheart rate.

A variety of stimulation therapies may be provided in embodiments of thepresent disclosure. Different nerve fiber types (e.g., A, B, andC-fibers that may be targeted) respond differently to stimulation fromelectrical signals because they have different conduction velocities andstimulation threshold. Certain pulses of an electrical stimulationsignal, for example, may be below the stimulation threshold for aparticular fiber and, therefore, may generate no action potential. Thus,smaller or narrower pulses may be used to avoid stimulation of certainnerve fibers (such as C-fibers) and target other nerve fibers (such as Aand/or B fibers, which generally have lower stimulation thresholds andhigher conduction velocities than C-fibers). Additionally, techniquessuch as a pre-pulse may be employed wherein axons of the target neuralstructure may be partially depolarized (e.g., with a pre-pulse orinitial phase of a pulse) before a greater current is delivered to thetarget (e.g., with a second pulse or an initial phase such a stair steppre-pulse to deliver a larger quantum of charge). Furthermore, opposingpolarity phases separated by a zero current phase may be used to exciteparticular axons or postpone nerve fatigue during long term stimulation.

Cranial nerve stimulation, such as vagus nerve stimulation (VNS), hasbeen proposed to treat a number of medical conditions, includingepilepsy and other movement disorders, depression and otherneuropsychiatric disorders, dementia, traumatic brain injury, coma,migraine headache, obesity, eating disorders, sleep disorders, cardiacdisorders (such as congestive heart failure and atrial fibrillation),hypertension, endocrine disorders (such as diabetes and hypoglycemia),and pain, among others. See, e.g., U.S. Pat. Nos. 4,867,164; 5,299,569;5,269,303; 5,571,150; 5,215,086; 5,188,104; 5,263,480; 6,587,719;6,609,025; 5,335,657; 6,622,041; 5,916,239; 5,707,400; 5,231,988; and5,330,515. Despite the variety of disorders for which cranial nervestimulation has been proposed or suggested, the fact that detailedneural pathways for many (if not all) cranial nerves remain relativelyunknown, makes predictions of efficacy for any given disorder difficultor impossible. Even if such pathways were known, the precise stimulationparameters that would modulate particular pathways relevant to aparticular disorder generally cannot be predicted.

Cardiac signals suitable for use in embodiments of the presentdisclosure may comprise one or more of an electrical (e.g., EKG),acoustic (e.g., phonocardiogram or ultrasound/ECHO), force or pressure(e.g., apexcardiogram), arterial pulse pressure and waveform or thermalsignals that may be recorded and analyzed to extract features such asheart rate, heart rate variability, rhythm (regular, irregular, sinus,ventricular, ectopic, etc.), morphology, etc.

It appears that sympatho-vagal imbalance (lower vagal and highersympathetic tone) plays an important role in generation of a widespectrum of ictal and interictal alterations in cardiac dynamics,ranging from rare unifocal PVCs to cardiac death. Without being bound bytheory, restoration of the vagal tone to a level sufficient tocounteract the pathological effects of elevated catecholamines may servea cardio-protective purpose that would be particularly beneficial inpatients with pharmaco-resistant epilepsies, who are at highest risk forSUDEP.

In one embodiment, the present disclosure provides methods and apparatusto increase cardiac vagal tone in epilepsy patients by timely deliveringtherapeutic electrical currents to the trunks of the right or left vagusnerves or to their cardiac rami (branches), in response to increases insympathetic tone, by monitoring among others, heart rate, heart rhythm,EKG morphology, blood pressure, skin resistance, catecholamine or theirmetabolites and neurological signals such as EEG/ECoG, kinetic (e.g.,amplitude velocity, direction of movements) and cognitive (e.g., complexreaction time).

In one embodiment, the present disclosure provides a method of treatinga medical condition selected from the group consisting of epilepsy,neuropsychiatric disorders (including but not limited to depression),eating disorders/obesity, traumatic brain injury, addiction disorders,dementia, sleep disorders, pain, migraine, endocrine/pancreaticdisorders (including but not limited to diabetes), motility disorders,hypertension, congestive heart failure/cardiac capillary growth, hearingdisorders, angina, syncope, vocal cord disorders, thyroid disorders,pulmonary disorders, gastrointestinal disorders, kidney disorders, andreproductive endocrine disorders (including infertility).

FIGS. 1A-1E depict a stylized implantable medical system 100 forimplementing one or more embodiments of the present disclosure. FIGS. 1Aand 1B illustrate an electrical signal generator 110 having main body112 comprising a case or shell (commonly referred to as a “can”) 121)(FIG. 1B) with a header 116 for connecting to a lead assembly 122. Anelectrode assembly 125, preferably comprising at least an electrodepair, is conductively connected to the distal end of an insulated,electrically conductive lead assembly 122, which preferably comprises aplurality of lead wires (at least one wire for each electrode of theelectrode assembly 125). Lead assembly 122 is attached at its proximalend to one or more connectors on header 116 (FIG. 1B).

Electrode assembly 125 may be surgically coupled to a target tissue fordelivery of a therapeutic electrical signal, which may be a pulsedelectrical signal. The target tissue may be a cranial nerve, such as avagus nerve 127 (FIGS. 1A, 1C-E) or another cranial nerve such as atrigeminal nerve. Electrode assembly 125 includes one or more electrodes125-1, 125-2, 125-3, which may be coupled to the target tissue. Theelectrodes may be made from any of a variety of conductive metals knownin the art, e.g., platinum, iridium, oxides of platinum or iridium, orcombinations of the foregoing. In one embodiment, the target tissue is avagus nerve 127, which may include an upper main trunk portion 127-1above a cardiac branch 127-2, and a lower main trunk portion 127-3 belowthe cardiac branch.

In one embodiment, at least one electrode may be coupled to the maintrunk of the vagus nerve, and at least one electrode 125-2 may becoupled to a cardiac branch 127-2 of the vagus nerve (FIG. 1C). The atleast one main trunk electrode may be coupled to an upper main trunk127-1 (e.g., electrode 125-1, FIG. 1C) or a lower main trunk 127-3(e.g., electrode 125-3). The at least one main trunk electrode (125-1,125-3) may be used as a cathode to provide a first electrical signal tothe upper (127-1) or lower (127-3) main trunk. Cardiac branch electrode125-2 may be used as a cathode to provide a second electrical signal tocardiac branch 127-2. An additional electrode to function as the anodemay be selected from one or more of the other electrodes in electrodeassembly 125, can 121, or a dedicated anode.

In some embodiments (FIGS. 1D, 1E), electrode assembly 125 may include amain trunk electrode pair comprising a cathode 125-1 a and an anode125-1 b for coupling to a main trunk of a vagus nerve 127. The maintrunk electrode pair 125-1 a, 125-1 b may be coupled to an upper maintrunk 127-1 of a vagus nerve (FIG. 1D), or to a lower main trunk 127-3(FIG. 1E) for delivering a first electrical signal. Without being boundby theory, it is believed that few or no vagal afferent fibers in thelower main trunk 127-3 pass into cardiac branch 127-2 and, accordingly,that effects of the first electrical signal on cardiac function may beminimized by coupling electrode pair 125-1 a and 125-1 b to the lowermain trunk 127-3 instead of upper main trunk 127-1. Cardiac effects mayalso be minimized by alternative embodiments in which the firstelectrical signal is applied to a lower main trunk 127-3 using a singleelectrode (e.g., 125-3, FIG. 1C) as a cathode and an anode that is notcoupled to the vagus nerve 127 (e.g., by using can 121 as an anode).

In some embodiments (FIGS. 1D, 1E), electrode assembly 125 may include acardiac branch electrode pair comprising a cathode 125-2 a and an anode125-2 b for coupling to a cardiac branch of a vagus nerve. The secondcardiac branch electrode pair may be used to provide a second electricalsignal to a cardiac branch of the nerve to affect the cardiac functionof the patient.

Referring again to FIGS. 1C-1E, a first electrical signal may beprovided to generate afferent action potentials in a main trunk of avagus nerve to modulate electrical activity of the patient's brainwithout significantly affecting the patient's heart rate. The secondelectrical signal may generate efferent action potentials to module thecardiac activity of the patient, and in particular to slow the patient'sheart rate (e.g., to treat an epilepsy patient having seizurescharacterized by ictal tachycardia) and maintain or restore asympathetic/parasympathetic balance to a non-pathological state. Thefirst electrical signal may be applied to the main trunk of the vagusnerve in a variety of ways, so long as at least one electrode is coupledto the main trunk as a cathode. As noted, the cathode may be coupled toeither an upper (127-1) or lower (127-3) main trunk, and an anode may beprovided by any of the other electrodes on the vagus nerve (e.g., 125-1b, 125-2 b, 125-3, FIGS. 1C-1E) or by a separate anode not coupled tothe vagus nerve (e.g., can 121). In one alternative embodiment, anelectrode 125-3 may be coupled to a lower main trunk 127-3 of the vagusnerve to function as an anode. In yet another embodiment, eachindividual electrode element in FIGS. 1A-E (e.g., 125-1, 125-2, 125-3,125-1 a, 125-1 g, 125-2 a, 125-2 b) may comprise an electrode paircomprising both an anode and a cathode. In an additional embodiment,each individual electrode element may comprise three electrodes (e.g.,one serving as cathode and the other two as anodes). Suitable electrodeassemblies are available from Cyberonics, Inc., Houston, Tex., USA asthe Model 302, PerenniaFlex and PerenniaDura electrode assemblies. Inview of the present disclosure, persons of skill in the art willappreciate that many electrode designs could be used in embodiments ofthe present disclosure including unipolar electrodes.

Embodiments of the present disclosure may comprise electrical signalswith either charge-balanced or non-charge-balanced pulses (e.g.,monopolar/monophasic, direct current (DC)). Charge-balanced pulsesinvolve a first phase in which the stimulation occurs (i.e., actionpotentials are induced in target nerve fibers), and a second phase inwhich the polarity of the electrodes are reversed (i.e., the stimulationphase cathode becomes the charge-balancing phase anode, and vice versa).The result is a pulse having two opposite-polarity phases of equalcharge, such that no net charge flows across the electrode during apulse. Charge-balancing is often used to avoid damage to the electrodesthat may result if a pulse results in a net charge flowing across theelectrodes.

In some instances, charge-balancing may involve a passive dischargephase as illustrated in, e.g., FIG. 1A of US Publication 2006/0173493,which is hereby incorporated by reference in its entirety. In passivecharge-balancing, the charge-balancing phase typically involves allowinga capacitor having a charge equal to the charge applied to the nerveduring the stimulation phase to discharge through the polarity-reversedelectrodes. Passive charge-balancing typically uses much lower initialcurrent than the stimulation phase, with the current declining to zeroover a much longer time period than the pulse width of the stimulationphase. A lower current is typically selected in the charge-balancingphase so as to avoid or minimize nerve recruitment during thecharge-balancing phase. In active charge-balancing, the charge-balancingphase is not accomplished by the passive discharge of a capacitor, butby providing a second phase having an opposite polarity but the samecharge magnitude (pulse width multiplied by current) as the first phase.As is usually the case with passive charge-balancing, activecharge-balancing typically involves a much lower current that is appliedover a longer time period than the stimulation phase, so as to avoidnerve recruitment. In some instances, however, the activecharge-balancing phase may be used as a second stimulation phase byselecting a current magnitude of the cathode in the charge-balancingphase (typically a second electrode, which may be the anode of theinitial stimulation phase) that is sufficient to generate actionpotentials in nerve fibers of the target tissue.

Embodiments of the present disclosure may be implemented using passivecharge balancing or active charge-balancing, and the latter may beprovided as a stimulation phase or a non-stimulation phase. Someembodiments may be implemented with non-charge-balanced pulses. Personsof skill in the art, having the benefit of the present disclosure, mayselect the type of charge balancing (if desired) based upon a number offactors including but not limited to whether or not the charge-balancingis intended to affect the cardiac cycle or not, whether afferent orefferent stimulation is desired, the number and location of availableelectrodes for applying the electrical signal, the fibers intended to berecruited during a particular phase and their physiological effects,among many other factors.

In the discussion of electrical signals in the present disclosure,unless otherwise stated, references to electrodes as cathodes or anodesrefers to the polarities of the electrodes during a stimulation phase ofa pulse, whether the pulse is a charge-balanced pulse or anon-charge-balanced pulse (e.g., monopolar/monophasic or DC). It will beappreciated that where charge-balanced pulses are employed, thepolarities will be reversed during a charge-balancing phase. Whereactive charge-balancing is used, cardiac effects may be furtheramplified or ameliorated, depending upon the location of the electrodesbeing used.

Returning to FIG. 1A, in some embodiments, a heart rate sensor 130,and/or a kinetic sensor 140 (e.g., a triaxial accelerometer) may beincluded in the system 100 to sense one or more of a cardiac signal ordata stream and a kinetic data stream of the patient. In one embodiment,the heart rate sensor may comprise a separate element 130 that may becoupled to generator 110 through header 116 as illustrated in FIG. 1A.In another embodiment, the electrodes 125-1, 125-2, 125-3 and/or the can121 may be used as sensing electrodes to sense heart rate. Anaccelerometer may be provided inside generator 110 in one embodiment tosense a kinetic signal (e.g., body movement) of the patient. One or moreof the heart rate sensor 130 and the kinetic sensor 140 may be used by aseizure detection algorithm in the system 100 to detect epilepticseizures. In alternative embodiments, other body signals (e.g., bloodpressure, brain activity, blood oxygen/CO₂ concentrations, temperature,skin resistivity, etc.) of the patient may be sensed and used by theseizure detection algorithm to detect epileptic seizures. Signalgenerator 110 may be implanted in the patient's chest in a pocket orcavity formed by the implanting surgeon below the skin (indicated byline 145, FIG. 1A).

Returning to FIGS. 1A and 1C, a first electrode 125-1 may be wrapped orotherwise electrically coupled to an upper main trunk 127-1 of a vagusnerve 127 of the patient, and a second electrode 125-2 may be wrapped orcoupled to a cardiac branch 127-2 of the vagus nerve. In one embodiment,a third electrode 125-3 may be coupled to a lower main trunk 127-3 ofthe vagus nerve below the cardiac branch 127-2 of the vagus nerve,instead of or in addition to first electrode 125-1 coupled to the uppermain trunk above the cardiac branch. In some embodiments, thirdelectrode 125-3 may be omitted. Electrode assembly 125 may be secured tothe nerve by a spiral anchoring tether 128 (FIG. 1C), which in oneembodiment does not include an electrode but in alternative embodimentsmay contain up to three electrodes that serve as cathode(s) and anode(s)in any possible combination. Lead assembly 122 may further be secured,while retaining the ability to flex, by a suture connection 130 tonearby tissue (FIG. 1C). In particular embodiments, any of first, secondand third electrodes 125-1, 125-2, and 125-3 may be used as either acathode or as an anode. In general, the foregoing electrodes may be usedas a cathode when the particular electrode is the closest electrode(among a plurality of electrodes) to the target organ (e.g., heart,brain, stomach, liver, etc.) to be stimulated. While a single electrode(e.g., 125-1, 125-2, or 125-3) is illustrated in connection with uppermain trunk 127-1, cardiac branch 127-2, and lower main trunk 127-3 inFIGS. 1A and 1C for simplicity, it will be appreciated that one or moreadditional electrodes can be provided on each of the foregoing neuralstructures to provide greater flexibility in stimulation.

In one embodiment, the open helical design of the electrodes 125-1,125-2, 125-3, is self-sizing, flexible, minimize mechanical trauma tothe nerve and allow body fluid interchange with the nerve. The electrodeassembly 125 preferably conforms to the shape of the nerve, providing alow stimulation threshold by allowing a large stimulation contact areawith the nerve. Structurally, the electrode assembly 125 comprises anelectrode ribbon (not shown) for each of electrodes 125-1, 125-2, 125-3,made of a conductive material such as platinum, iridium,platinum-iridium alloys, and/or oxides thereof. The electrode ribbonsare individually bonded to an inside surface of an elastomeric bodyportion of the spiral electrodes 125-1, 125-2, 125-3 (FIG. 1C), whichmay comprise spiral loops of a multi-loop helical assembly. Leadassembly 122 may comprise three distinct lead wires or a triaxial cablethat are respectively coupled to one of the conductive electroderibbons. One suitable method of coupling the lead wires to theelectrodes 125-1, 125-2, 125-3 comprises a spacer assembly such as thatdisclosed in U.S. Pat. No. 5,531,778, although other known couplingmethods may be used.

The elastomeric body portion of each loop may be composed of siliconerubber or other biocompatible elastomeric compounds, and the fourth loop128 (which may have no electrode in some embodiments) acts as theanchoring tether for the electrode assembly 125.

In one embodiment, electrical pulse generator 110 may be programmed withan external computer 150 using programming software known in the art forstimulating neural structures, and a programming wand 155 to facilitateradio frequency (RF) communication between the external computer 150(FIG. 1A) and the implanted pulse generator 110. In one embodiment, wand155 and software permit wireless, non-invasive communication with thegenerator 110 after surgical implantation. Wand 155 may be powered byinternal batteries, and provided with a “power on” light to indicatesufficient power for communications. Another indicator light may beprovided to show that data transmission is occurring between the wandand the generator. In other embodiments, wand 155 may be omitted, e.g.,where communications occur in the 401-406 MHz bandwidth for MedicalImplant Communication Service (MICS band).

In some embodiments of the disclosure, a body data stream may beanalyzed to determine whether or not a seizure has occurred. Manydifferent body data streams and seizure detection indices have beenproposed for detecting epileptic seizures. Additional details on methodof detecting seizure from body data are provided in U.S. Pat. Nos.8,337,404 and 8,382,667, both issued in the name of the presentapplicant and both entitled, “Detecting, Quantifying, and/or ClassifyingSeizures Using Multimodal Data,” as well as in co-pending U.S. patentapplication Ser. No. 13/288,886, filed Nov. 3, 2011, each herebyincorporated by reference in its entirety herein. Seizure detectionbased on the patient's heart rate (as sensed by implanted or externalelectrodes), movement (as sensed by, e.g., a triaxial accelerometer),responsiveness, breathing, blood oxygen saturation, skinresistivity/conductivity, temperature, brain activity, and a number ofother body data streams are provided in the foregoing patents andco-pending applications.

In one embodiment, the present disclosure provides a method for treatinga patient with epilepsy in which a body data stream is analyzed using aseizure detection algorithm to determine whether or not the patient hashad an epileptic seizure. As used herein, the term “has had an epilepticseizure” includes instances in which a seizure onset has been detected,as well as instances in which the seizure onset has been detected andthe seizure is still ongoing (i.e., the seizure has not ended). If theanalysis results in a determination that the patient has not had anepileptic seizure, a signal generator may apply a first electricalsignal to a main trunk of a vagus nerve of the patient. If the analysisresults in a determination that the patient has had an epilepticseizure, the signal generator may apply a second electrical signal to acardiac branch of a vagus nerve of the patient. In some embodiments, theapplication of the first electrical signal to the main trunk isterminated, and only the second electrical signal to the cardiac branchis provided once a seizure is detected.

In alternative embodiments, both the first and second electrical signalsmay be applied to the main trunk and cardiac branch, respectively, ofthe vagus nerve in response to a determination that the patient has hada seizure (i.e., the first electrical signal continues to be applied tothe main trunk of the vagus nerve and the second signal is initiated).Where both the first and second electrical signals are provided, the twosignals may be provided sequentially, or in alternating fashion to themain trunk and the cardiac branch. In one embodiment, the first signalmay be provided to the main trunk by using one of the upper main trunkelectrode 125-1 or the lower main trunk electrode 125-3 as the cathodeand the cardiac branch electrode 125-2 as the anode, or by using both ofthe upper main trunk electrode and the lower main trunk electrode as thecathode and the anode. The second signal may be provided (e.g., byrapidly changing the polarity of the electrodes) by using the cardiacbranch electrode 125-2 as the cathode and a main trunk electrode 125-1or 125-3 as the anode.

In still other embodiments, the second electrical signal is applied tothe cardiac branch of the vagus nerve only if the analysis results in adetermination that the patient is having and/or has had an epilepticevent that is accompanied by an increase in heart rate, and the secondelectrical signal is used to lower the heart rate back towards a ratethat existed prior to the seizure onset. Without being bound by theory,the present inventors believe that slowing the heart rate at the onsetof seizures—particularly where the seizure is accompanied by an increasein heart rate—may improve the ability of VNS therapy to providecardio-protective benefits.

Prior patents describing vagus nerve stimulation as a medical therapyhave cautioned that undesired slowing of the heart rate may occur, andhave proposed various methods of avoiding such a slowing of the heartrate. In U.S. Pat. No. 6,341,236, it is suggested to sense heart rateduring delivery of VNS and if a slowing of the heart rate is detected,either suspending delivery of the VNS signal or pacing the heart using apacemaker. The present application discloses a VNS system that detectsepileptic seizures, particularly epileptic seizures accompanied by anincrease in heart rate, and intentionally applies an electrical signalto slow the heart rate in response to such a detection. In anotheraspect, the present application discloses VNS systems that provide afirst electrical signal to modulate only the brain during periods inwhich no seizure has been detected, and either 1) a second electricalsignal to modulate only the heart (to slow its rate) or 2) both a firstelectrical signal to the brain and a second electrical signal to theheart, in response to a detection of the onset of an epileptic seizure.These electrical signals may be delivered simultaneously, sequentially(e.g., delivery of stimulation to the brain precedes delivery ofstimulation to the heart or vice versa), or delivery of the first andsecond signals may be interspersed or interleaved.

The first electrode may be used as a cathode to provide an afferentfirst electrical signal to modulate the brain of the patient via maintrunk electrode 125-1. Electrode 125-1 may generate both afferent andefferent action potentials in vagus nerve 127. One or more of electrodes125-2 and 125-3 are used as anodes to complete the circuit. Where thisis the case, some of the action potentials may be blocked at theanode(s), with the result that the first electrical signal maypredominantly modulate the brain by afferent actions traveling towardthe brain, but may also modulate one or more other organs by efferentaction potentials traveling toward the heart and/or lower organs, to theextent that the efferent action potentials are not blocked by theanode(s).

The second electrode may be used as a cathode to provide an efferentsecond electrical signal to slow the heart rate of the patient viacardiac branch electrode 125-2. Either first electrode 125-1 or a thirdelectrode 125-3 (or can 121) may be used as an anode to complete thecircuit. In one embodiment, the first electrical signal may be appliedto the upper (127-1) or lower (127-3) main trunk of the vagus nerve inan open-loop manner according to programmed parameters including anoff-time and an on-time. The on-time and off-time together establish theduty cycle determining the fraction of time that the signal generatorapplies the first electrical. In one embodiment, the off-time may rangefrom 7 seconds to several hours or even longer, and the on-time mayrange from 5 seconds to 300 seconds. It should be noted that the dutycycle does not indicate when current is flowing through the circuit,which is determined from the on-time together with the pulse frequency(usually 10-200, Hz, and more commonly 20-30 Hz) and pulse width(typically 0.1-0.5 milliseconds). The first electrical signal may alsobe defined by a current magnitude (e.g., 0.25-3.5 milliamps), andpossibly other parameters (e.g., pulse width, and whether or not acurrent ramp-up and/or ramp-down is provided, a frequency, and a pulsewidth.

In one embodiment, a seizure detection may result in both applying thefirst electrical signal to provide stimulation to the brain in closeproximity to a seizure detection (which may interrupt or terminate theseizure), as well as application of the second electrical signal whichmay slow the heart, thus exerting a cardio-protective effect. In aparticular embodiment, the second electrical signal is applied only inresponse to a seizure detection that is characterized by (or accompaniedor associated with) an increase in heart rate, and is not applied inresponse to seizure detections that are not characterized by an increasein heart rate. In this manner, the second electrical signal may helpinterrupt the seizure by restoring the heart to a pre-seizure baselineheart rate when the patient experiences ictal tachycardia (elevatedheart rate during the seizure), while leaving the heart rate unchangedif the seizure has no significant effect on heart rate.

In still further embodiments, additional logical conditions may beestablished to control when the second electrical signal is applied tolower the patient's heart rate following a seizure detection. In oneembodiment, the second electrical signal is applied only if themagnitude of the ictal tachycardia rises above a defined level. In oneembodiment, the second electrical signal is applied to the cardiacbranch only if the heart rate increases by a threshold amount above thepre-ictal baseline heart rate (e.g., more than 20 beats per minute abovethe baseline rate). In another embodiment, the second electrical signalis applied to the cardiac branch only if the heart rate exceeds anabsolute heart rate threshold (e.g., 100 beats per minute, 120 beats perminute, or other programmable threshold). In a further embodiment, aduration constraint may be added to one or both of the heart rateincrease or absolute heart rate thresholds, such as a requirement thatthe heart rate exceed the baseline rate by 20 beats per minute for morethan 10 seconds, or exceed 110 beats per minute for more than 10seconds, before the second electrical signal is applied to the cardiacbranch in response to a seizure detection.

In another embodiment, the heart rate sensor continues to monitor thepatient's heart rate during and/or after application of the secondelectrical signal, and the second electrical signal is interrupted orterminated if the patient's heart rate is reduced below a low heart ratethreshold, which may be the baseline heart rate that the patientexperienced prior to the seizure, or a rate lower or higher than thebaseline pre-ictal heart rate. The low rate threshold may provide ameasure of safety to avoid undesired events such as bradycardia and/orsyncope.

In yet another embodiment, heart rate sensor 130 may continue to monitorheart rate and/or kinetic sensor 140 may continue to monitor bodymovement in response to applying the second electrical signal, and thesecond electrical signal may be modified (e.g., by changing one or moreparameters such as pulse frequency, or by interrupting and re-initiatingthe application of the second electrical signal to the cardiac branch ofthe vagus nerve) to control the heart rate below an upper heart ratethreshold and/or body movement exceeds one or more movement thresholds.For example, the frequency or duration of the second electrical signalapplied to the cardiac branch of the vagus nerve may be continuouslymodified based the instantaneous heart rate as monitored during thecourse of a seizure to control what would otherwise be an episode ofictal tachycardia below an upper heart rate threshold. In one exemplaryembodiment, the second electrical signal may be programmed to provide a30-second pulse burst at 30 Hz, with the pulses having a pulse width of0.25 milliseconds and a current of 1.5 milliamps. If, at the end of the30 second burst, the heart rate remains above 120 beats per minute, andis continuing to rise, the burst may be extended to 1 minute instead of30 seconds, the frequency may be increased to 50 Hz, the pulse width maybe increased to 350 milliseconds, or combinations of the foregoing. Instill further embodiments, additional therapies (e.g., oxygen delivery,drug delivery, cooling therapies, etc.) may be provided to the patientif the body data (heart rate, kinetic activity, etc.) indicates that thepatient's seizure is not under control or terminated.

Abnormalities or changes in EKG morphology or rhythm relative to aninterictal morphology or rhythm may also trigger delivery of current tothe heart via the trunks of vagi or its cardiac rami. In otherembodiments, pharmacological agents such as beta-blockers may beautomatically released into a patient's blood stream in response to thedetection of abnormal heart activity during or between seizures.

In one embodiment, the first electrical signal and the second electricalsignal are substantially identical. In another embodiment, the firstelectrical signal may vary from the second electrical signal in terms ofone or more of pulse width, number of pulses, amplitude, frequency,inter-pulse-interval, stimulation on-time, and stimulation off-time,among other parameters and degree, rate or type of charge balancing.

The number of pulses applied to the main trunk or cardiac branch,respectively, before changing the polarity of the first and secondelectrodes need not be one. Thus, two or more pulses may be applied tothe main trunk before applying pulses to the cardiac branch of the vagusnerve. More generally, the first and second signals can be independentof one another and applied according to timing and programmingparameters controlled by the controller 210 and stimulation unit 220.

In one embodiment, one or more pulse bursts of the first electricalsignal are applied to the main trunk of the vagus nerve in response to adetected seizure before applying one or more bursts of the secondelectrical signal to the cardiac branch. In another embodiment, thefirst and second signals are interleaved on a pulse-by-pulse basis underthe control of the controller 210 and stimulation unit 220.

Typically, VNS can be performed with pulse frequency of 20-30 Hz(resulting in a number of pulses per burst of 140-1800, at a burstduration from 7-60 sec). In one embodiment, at least one of the firstelectrical signal and the second electrical signal comprises amicroburst signal. Microburst neurostimulation is discussed by U.S. Ser.No. 11/693,451, filed Mar. 2, 2007 and published as United States patentPublication No. 20070233193, and incorporated herein by reference in itsentirety. In one embodiment, at least one of the first electricalsignal, the second electrical signal, and the third electrical signal ischaracterized by having a number of pulses per microburst from 2 pulsesto about 25 pulses, an interpulse interval of about 2 msec to about 50msec, an interburst period of at least 100 msec, and a microburstduration of less than about 1 sec.

Cranial nerves such as the vagus nerve include different types of nervefibers, such as A-fibers, B-fibers and C-fibers. The different fibertypes propagate action potentials at different velocities. Each nervefiber is directional—that is, endogenous or natural action potentialscan generally propagate action potentials in only one direction (e.g.,afferently to the brain or efferently to the heart and/or viscera). Thatdirection is referred to as the orthodromic direction. Exogenousstimulation (e.g., by electrical pulses) may induce action potentials inboth the orthodromic direction as well as the antidromic direction.Depending upon the desired effects of stimulation (e.g., afferentmodulation of the brain, efferent modulation of the heart, etc.) certainmeasures (e.g., cooling, pressure, etc.) may be taken to blockpropagation in either the efferent or the afferent direction. It isbelieved that the anode may block at least some action potentialstraveling to it from the cathode. For example, referring to FIG. 1, bothafferent and efferent action potentials may be generated in an uppermain trunk of vagus nerve 127-1 by applying a pulse to the nerve usingupper main trunk electrode 125-1 as a cathode. Action potentialsgenerated at upper main trunk electrode 125-1 and traveling toward theheart on cardiac branch 127-2 may be blocked by cardiac branch anode125-2. Action potentials traveling from the upper main trunk 127-1 tothe lower organs in lower main trunk 127-3 may be either blocked (byusing lower main trunk electrode 125-3 as an anode either with orinstead of cardiac branch electrode 125-2) or allowed to travel to thelower organs (by not using electrode structure 125-3 as an electrode).

Action potentials may be generated and allowed to travel to the heart bymaking the electrode 125-2 the cathode. If cardiac branch electrode125-2 is used as a cathode, action potentials will reach the heart inlarge numbers, while action potentials traveling afferently toward thebrain may be blocked in the upper trunk if upper electrode 125-1 is madethe anode.

In a further embodiment of the disclosure, rapid changes in electrodepolarity may be used to generate action potentials to collision blockaction potentials propagating in the opposite direction. To generalize,in some embodiments, the vagus nerve can be selectively stimulated topropagate action potentials either afferently (i.e., to the brain) orefferently (i.e., to the heart and/or lower organs/viscerae).

Turning now to FIG. 2, a block diagram depiction of an implantablemedical device, in accordance with one illustrative embodiment of thepresent disclosure is illustrated. The IMD 200 may be coupled to variouselectrodes 125 and/or 127 via lead(s) 122 (FIGS. 1A, 1C). First andsecond electrical signals used for therapy may be transmitted from theIMD 200 to target areas of the patient's body, specifically to variouselectrodes associated with the leads 122. Stimulation signals from theIMD 200 may be transmitted via the leads 122 to stimulation electrodes(electrodes that apply the therapeutic electrical signal to the targettissue) associated with the electrode assembly 125, e.g., 125-1, 125-2,125-3 (FIG. 1A).

The IMD 200 may comprise a controller 210 capable of controlling variousaspects of the operation of the IMD 200. The controller 210 is capableof receiving internal data and/or external data and controlling thegeneration and delivery of a stimulation signal to target tissues of thepatient's body. For example, the controller 210 may receive manualinstructions from an operator externally, may perform stimulation basedon internal calculations and programming, and may receive and/or processsensor data received from one or more body data sensors such aselectrodes 125-1, 125-2, 125-3, or heart rate sensor 130. The controller210 is capable of affecting substantially all functions of the IMD 200.

The controller 210 may comprise various components, such as a processor215, a memory 217, etc. The processor 215 may comprise one or more microcontrollers, microprocessors, etc., that are capable of executing avariety of software components. The processor may receive, pre-conditionand/or condition sensor signals, and may control operations of othercomponents of the IMD 200, such as stimulation unit 220, seizuredetection module 240, logic unit 250, communication unit, 260, andelectrode polarity reversal unit 280. The memory 217 may comprisevarious memory portions, where a number of types of data (e.g., internaldata, external data instructions, software codes, status data,diagnostic data, etc.) may be stored. The memory 217 may store varioustables or other database content that could be used by the IMD 200 toimplement the override of normal operations. The memory 217 may compriserandom access memory (RAM) dynamic random access memory (DRAM),electrically erasable programmable read-only memory (EEPROM), flashmemory, etc.

The IMD 200 may also comprise a stimulation unit 220. The stimulationunit 220 is capable of generating and delivering a variety of electricalsignal therapy signals to one or more electrodes via leads. Thestimulation unit 220 is capable of delivering a programmed, firstelectrical signal to the leads 122 coupled to the IMD 200. Theelectrical signal may be delivered to the leads 122 by the stimulationunit 220 based upon instructions from the controller 210. Thestimulation unit 220 may comprise various types of circuitry, such asstimulation signal generators, impedance control circuitry to controlthe impedance “seen” by the leads, and other circuitry that receivesinstructions relating to the type of stimulation to be performed.

Signals from sensors (electrodes that are used to sense one or more bodyparameters such as temperature, heart rate, brain activity, etc.) may beprovided to the IMD 200. The body signal data from the sensors may beused by a seizure detection algorithm embedded or processed in seizuredetection module 240 to determine whether or not the patient is havingand/or has had an epileptic seizure. The seizure detection algorithm maycomprise hardware, software, firmware or combinations thereof, and mayoperate under the control of the controller 210. Although not shown,additional signal conditioning and filter elements (e.g., amplifiers,D/A converters, etc., may be used to appropriately condition the signalfor use by the seizure detection module 240. Sensors such as heartsensor 130 and kinetic sensor 140 may be used to detect seizures, alongwith other autonomic, neurologic, or other body data.

The IMD 200 may also comprise an electrode polarity reversal unit 280.The electrode polarity reversal unit 280 is capable of reversing thepolarity of electrodes (125-1, 125-2, 125-3) associated with theelectrode assembly 125. The electrode polarity reversal unit 280 isshown in more detail in FIG. 3. In preferred embodiments, the electrodepolarity reversal unit is capable of reversing electrode polarityrapidly, i.e., in about 10 microseconds or less, and in any event at asufficiently rapid rate to permit electrode polarities to be changedbetween adjacent pulses in a pulsed electrical signal.

The IMD 200 may also comprise a power supply 230. The power supply 230may comprise a battery, voltage regulators, capacitors, etc., to providepower for the operation of the IMD 200, including delivering thestimulation signal. The power supply 230 comprises a power-sourcebattery that in some embodiments may be rechargeable. In otherembodiments, a non-rechargeable battery may be used. The power supply230 provides power for the operation of the IMD 200, includingelectronic operations and the stimulation function. The power supply 230may comprise a lithium/thionyl chloride cell or a lithium/carbonmonofluoride (LiCFx) cell. Other battery types known in the art ofimplantable medical devices may also be used.

The IMD 200 also comprises a communication unit 260 capable offacilitating communications between the IMD 200 and various devices. Inparticular, the communication unit 260 is capable of providingtransmission and reception of electronic signals to and from an externalunit 270. The external unit 270 may be a device that is capable ofprogramming various modules and stimulation parameters of the IMD 200.In one embodiment, the external unit 270 comprises a computer systemthat is capable of executing a data-acquisition program. The externalunit 270 may be controlled by a healthcare provider, such as aphysician, at a base station in, for example, a doctor's office. Theexternal unit 270 may be a computer, preferably a handheld computer orPDA, but may alternatively comprise any other device that is capable ofelectronic communications and programming. The external unit 270 maydownload various parameters and program software into the IMD 200 forprogramming the operation of the implantable device. The external unit270 may also receive and upload various status conditions and other datafrom the IMD 200. The communication unit 260 may be hardware, software,firmware, and/or any combination thereof. Communications between theexternal unit 270 and the communication unit 260 may occur via awireless or other type of communication, illustrated generally by line275 in FIG. 2.

In one embodiment, the communication unit 260 can transmit a log ofstimulation data and/or seizure detection data to the patient, aphysician, or another party.

In one embodiment, a method of treating an epileptic seizure is providedthat involves providing simultaneously both a first electrical signal toa main trunk of a vagus nerve and a second electrical signal to acardiac branch of the vagus nerve. As used herein “simultaneously”refers to the on-time of the first and second signals, and does notrequire that individual pulses of the first signal and the second signalbe simultaneously applied to target tissue. The timing of pulses for thefirst electrical signal and the second electrical signal may bedetermined by controller 210 in conjunction with stimulation unit 220.Where active charge-balancing is used, it may be possible to use theactive charge-balancing phase of pulses of the first electrical signalas the stimulation phase of the second electrical signal by selecting acurrent magnitude of the cathode in the charge-balancing phase(typically a second electrode, which may be the anode of the initialstimulation phase) that is sufficient to generate action potentials innerve fibers of the target tissue. Controller 210 may in someembodiments provide simultaneous delivery of first and second electricalsignals by interleaving pulses for each of the first and secondelectrical signals based upon the programmed timing of pulses for eachsignal and the appropriate polarity of each of first and secondelectrodes 125-1 and 125-2. In some embodiments, additional electrodesmay be used to minimize the induction of action potentials to the heartor the brain provided by the first electrical signal or the secondelectrical signal. This may be accomplished, in one embodiment, by usingan anode located on either the upper main trunk or the cardiac branch toblock impulse conduction to the heart or brain from the cathode, or byproviding dedicated electrode pairs on both the main trunk and cardiacbranches (FIGS. 1D, 1E). When beneficial, steps to avoid collisions ofactions potentials travelling in opposite directions may be implemented,while steps to promote collisions may be taken when clinicallyindicated. In some embodiments, the method further includes sensing acardiac signal and a kinetic signal of the patient, and detecting aseizure event with a seizure detection algorithm.

In one embodiment, a first electrical signal is applied to a main trunkof a vagus nerve and a second electrical signal is simultaneouslyapplied to a cardiac branch of a vagus nerve. A pulse of the firstelectrical signal is generated with the electrical signal generator 110and applied to the main trunk of the vagus nerve using a first electrode(e.g., 125-1, 125-1 a) as a cathode and a second electrode (e.g., 125-1b, 125-3, or 125-2) as an anode. The method includes sensing a cardiacsignal and a kinetic signal of the patient, and detecting a seizureevent with a seizure detection algorithm. A pulse of the secondelectrical signal (having the appropriate pulse width and current) isgenerated and applied (under appropriate timing control by controller110 and stimulation unit 220) to the cardiac branch of the vagus nerveusing a second electrode (e.g., 125-2. 125-2 a) as a cathode and anotherelectrode (e.g., 125-3, 125-1, 125-2 b) as an anode. Another pulse ofthe first electrical signal may thereafter be generated and applied tothe main trunk under timing and parameter control of controller 210 andstimulation unit 220. By appropriate selection of cathodes and anodes,the first and second electrical signals may be interleaved and providedsimultaneously to the main trunk and cardiac branches of the vagusnerve. In some embodiments, the number of electrodes may be minimized byprovided a polarity reversal unit that may rapidly change the polarityof particular electrodes to allow their use in delivering both the firstand second signals.

The IMD 200 is capable of delivering stimulation that can be contingent,periodic, random, coded, and/or patterned. The stimulation signals maycomprise an electrical stimulation frequency of approximately 0.1 to10,000 Hz. The stimulation signals may comprise a pulse width in therange of approximately 1-2000 micro-seconds. The stimulation signals maycomprise current amplitude in the range of approximately 0.1 mA to 10mA. Appropriate precautions may be taken to avoid delivering injuriouscurrent densities to target neural tissues, e.g., by selecting current,voltage, frequency, pulse width, on-time and off-time parameters tomaintain current density below thresholds for damaging tissues.

The IMD 200 may also comprise a magnetic field detection unit 290. Themagnetic field detection unit 290 is capable of detecting magneticand/or electromagnetic fields of a predetermined magnitude. Whether themagnetic field results from a magnet placed proximate to the IMD 200, orwhether it results from a substantial magnetic field encompassing anarea, the magnetic field detection unit 290 is capable of informing theIMD of the existence of a magnetic field. The changeable electrodepolarity stimulation described herein may be activated, deactivated, oralternatively activated or deactivated using a magnetic input.

The magnetic field detection unit 290 may comprise various sensors, suchas a Reed Switch circuitry, a Hall Effect sensor circuitry, and/or thelike. The magnetic field detection unit 290 may also comprise variousregisters and/or data transceiver circuits that are capable of sendingsignals that are indicative of various magnetic fields, the time periodof such fields, etc. In this manner, the magnetic field detection unit290 is capable of detecting whether the detected magnetic field relatesto an input to implement a particular first or second electrical signal(or both) for application to the main trunk of cardiac branches,respectively, of the vagus nerve.

One or more of the blocks illustrated in the block diagram of the IMD200 in FIG. 2, may comprise hardware units, software units, firmwareunits, or any combination thereof. Additionally, one or more blocksillustrated in FIG. 2 may be combined with other blocks, which mayrepresent circuit hardware units, software algorithms, etc.Additionally, one or more of the circuitry and/or software unitsassociated with the various blocks illustrated in FIG. 2 may be combinedinto a programmable device, such as a field programmable gate array, anASIC device, etc.

FIG. 3 shows in greater detail an electrode polarity reversal unit 280(FIG. 2) in one embodiment. The electrode polarity reversal unit 280comprises an electrode configuration switching unit 340, which includesa switching controller 345. The switching controller 345 transmitssignals to one or more switches, generically, n switches 330(1), 330(2),. . . 330(n) which effect the switching of the configuration of two ormore electrodes, generically, n electrodes 125(1), 125(2), . . . 125(n).Although FIG. 3 shows equal numbers of switches 330 and electrodes 125,persons of skill in the art having the benefit of the present disclosurewill understand that the number of switches 330 and their connectionswith the various electrodes 125 can be varied as a matter of routineoptimization. A switching timing unit 333 can signal to the electrodeconfiguration switching unit 340 that a desired time for switching theelectrode configuration has been reached.

Instructions for implementing two or more stimulation regimens, whichmay include at least one open-loop electrical signal and at least oneclosed-loop electrical signal, may be stored in the IMD 200. Thesestimulation signals may include data relating to the type of stimulationsignal to be implemented. In one embodiment, an open-loop signal may beapplied to generate action potentials for modulating the brain of thepatient, and a closed-loop signal may be applied to generate eitheraction potentials for slowing the heart rate of the patient, or bothaction potentials to modulate the brain of the patient as well as actionpotentials for slowing the heart rate of the patient. In someembodiments, the open-loop and closed-loop signals may be provided todifferent target portions of a vagus nerve of the patient by switchingthe polarity of two or more electrodes using an electrode polarityreversal unit as described in FIG. 3 above. In alternative embodiments,additional electrodes may be provided to generate each of the open-loopand closed-loop signals without electrode switching.

In one embodiment, a first open-loop mode of stimulation may be used toprovide an electrical signal to a vagus nerve using a first electrode asa cathode on a main trunk (e.g., 127-1 or 127-3 using electrodes 125-1or 125-3, respectively) of a vagus nerve, and a second electrode as ananode on either a main trunk (e.g., electrode 125-3, when electrode125-1 is used as a cathode) or cardiac branch (e.g., electrode 125-2) ofa vagus nerve. The first open-loop signal may include a programmedon-time and off-time during which electrical pulses are applied (theon-time) and not-applied (the off-time) in a repeating sequence to thevagus nerve.

A second, closed-loop signal may be provided in response to a detectedevent (such as an epileptic seizure, particularly when accompanied by anincrease in the patient's heart rate) using a different electrodeconfiguration than the first, open-loop signal. In one embodiment, thesecond, closed-loop signal is applied to a cardiac branch using thesecond electrode 125-2 as a cathode and the first electrode on the maintrunk (e.g., 125-1 or 125-3) as an anode. The second, closed-loop signalmay involve generating efferent action potentials on the cardiac branchof the vagus nerve to slow the heart rate. In some embodiments, thefirst, open-loop signal may be interrupted/suspended in response to thedetected event, and only the second, closed-loop signal is applied tothe nerve. In other embodiments, the first, open loop signal may not beinterrupted when the event is detected, and both the first, open-loopsignal and the second, closed-loop signal are applied to the vagusnerve. In another embodiment, a third, closed-loop signal may also beprovided in response to the detected event. The third, closed-loopsignal may involve an electrical signal using the same electrodeconfiguration as the first, open-loop electrical signal, but may providea different electrical signal to the main trunk of the vagus nerve thaneither the first, open-loop signal or the second, closed-loop signal.The first, open-loop signal may be interrupted, terminated or suspendedin response to the detected event, and the third, closed-loop signal maybe applied to the nerve either alone or with the second, closed-loopsignal. In some embodiments, both the second and third closed-loopsignals may be provided in response to a detected epileptic seizure byrapidly changing the polarity of the first (125-1) and second (125-2)electrodes from cathode to anode and back, as pulses are provided aspart of the second and third electrical signals, respectively. In oneembodiment, the third electrical signal may involve modulating the brainby using a main trunk electrode (e.g., upper main trunk electrode 125-1)as a cathode and another electrode (e.g., cardiac branch electrode 125-2or lower main trunk electrode 125-3) as an anode. The third electricalsignal may comprise, for example, a signal that is similar to the firstelectrical signal but which provides a higher electrical current thanthe first electrical signal, and for a longer duration than the firstsignal or for a duration that is adaptively determined based upon asensed body signal (in contrast, for example, to a fixed duration of thefirst electrical signal determined by a programmed on-time). By rapidlychanging polarity of the electrodes, pulses for each of the second andthird electrical signals may be provided such that the second and thirdsignals are provided simultaneously to the cardiac branch and main trunkof the vagus nerve. In other embodiments, the first, second and thirdelectrical signals may be provided sequentially rather thansimultaneously.

In some embodiments, one or more of the first, second and thirdelectrical signals may comprise a microburst signal, as described morefully in U.S. patent application Ser. Nos. 11/693,421, 11/693,451, and11/693,499, each filed Mar. 29, 2007 and each hereby incorporated byreference herein in their entirety.

In one embodiment, each of a plurality of stimulation regimens mayrespectively relate to a particular disorder, or to particular eventscharacterizing the disorder. For example, different electrical signalsmay be provided to one or both of the main trunk and cardiac branches ofthe vagus nerve depending upon what effects accompany the seizure. In aparticular embodiment, a first open-loop signal may be provided to thepatient in the absence of a seizure detection, while a second,closed-loop signal may be provided when a seizure is detected based on afirst type of body movement of the patient as detected by, e.g., anaccelerometer, a third, closed-loop signal may be provided when theseizure is characterized by a second type of body movement, a fourth,closed-loop signal may be provided when the seizure is characterized byan increase in heart rate, a fifth, closed-loop signal may be providedwhen the seizure is characterized by a decrease in heart rate, and soon. More generally, stimulation of particular branches or main trunktargets of a vagus nerve may be provided based upon different bodysignals of the patient. In some embodiments, additional therapies may beprovided based on different events that accompany the seizure, e.g.,stimulation of a trigeminal nerve or providing a drug therapy to thepatient through a drug pump. In one embodiment, different regimensrelating to the same disorder may be implemented to accommodateimprovements or regressions in the patient's present condition relativeto his or her condition at previous times. By providing flexibility inelectrode configurations nearly instantaneously, the present disclosuregreatly expands the range of adjustments that may be made to respond tochanges in the patient's underlying medical condition.

The switching controller 345 may be a processor that is capable ofreceiving data relating to the stimulation regimens. In an alternativeembodiment, the switching controller may be a software or a firmwaremodule. Based upon the particulars of the stimulation regimens, theswitching timing unit 333 may provide timing data to the switchingcontroller 345. The first through nth switches 330(1-n) may beelectrical devices, electro-mechanical devices, and/or solid statedevices (e.g., transistors).

FIG. 4 shows one embodiment of a method of treating a patient havingepilepsy according to the present disclosure. In this embodiment, afirst electrode is coupled to a main trunk of a vagus nerve of thepatient (410) and a second electrode is coupled to a cardiac branch ofthe vagus nerve (420). An electrical signal generator is coupled to thefirst and second electrodes (430).

The method further involves receiving at least one body data stream ofthe patient (440). The data may be sensed by a sensor such as heart ratesensor 130 (FIG. 1A) or a sensor that is an integral part of, or coupledto, an IMD 200 (FIG. 2) such as electrical pulse generator 110 (FIG.1A), and the IMD may also receive the data from the sensor. The at leastone body data stream is then analyzed using a seizure detectionalgorithm (450), and the seizure detection algorithm determines whetheror not the patient is having and/or has had an epileptic seizure (460).

If the algorithm indicates that the patient is not having and/or has nothad an epileptic seizure, the method comprises applying a firstelectrical signal from the electrical signal generator to the main trunkof a vagus nerve using the first electrode as a cathode (470). In oneembodiment, applying the first electrical signal comprises continuing toapply a programmed, open-loop electrical signal periodically to the maintrunk of the vagus nerve according a programmed on-time and off-time.

If the algorithm indicates that the patient is having and/or has had anepileptic seizure, the method comprises applying a second electricalsignal from the electrical signal generator to the cardiac branch of thevagus nerve using the second electrode as a cathode (480). Dependingupon which electrical signal (first or second) is applied, the methodmay involve changing the polarity of one or both of the first electrodeand the second electrode. In one embodiment, the method may comprisesuspending the first electrical and applying the second electricalsignal. In one embodiment, the method comprises continuing to receive atleast one body data stream of the patient at 440 after determiningwhether or not the patient is having and/or has had an epilepticseizure.

In an alternative embodiment, if the seizure detection algorithmindicates that the patient is having and/or has had an epilepticseizure, both the first electrical signal and the second electricalsignal are applied to the main trunk and cardiac branches of a vagusnerve of the patient, respectively, at step 480. In a specificimplementation of the alternative embodiment, pulses of the first andsecond electrical signal are applied to the main trunk and cardiacbranch of the vagus nerve under the control of controller 210 by rapidlychanging the polarity of the first and second electrodes using theelectrode polarity reversal unit 280 to apply the first electricalsignal to the main trunk using the first electrode as a cathode and thesecond electrode as an anode, changing the polarity of the first andsecond electrodes, and applying the second electrical signal to thecardiac branch using the second electrode as a cathode and the firstelectrode as an anode. Additional pulses for each signal may besimilarly applied by rapidly changing the polarity of the electrodes.

In some embodiments, the first electrical signal and the secondelectrical signal are applied unilaterally, i.e., to a vagal main trunkand a cardiac branch on the same side of the body. In other embodiments,the first and second electrical signals are applied bilaterally, i.e.,the second electrical signal is applied to a cardiac branch on theopposite side of the body from the main vagal trunk to which the firstelectrical signal is applied. In one embodiment, the first electricalsignal is applied to a left main trunk to minimize cardiac effects ofthe first electrical signal, and the second electrical signal is appliedto a right cardiac branch, which modulates the sinoatrial node of theheart to maximize cardiac effects of the second electrical signal.

In alternative embodiments, both the first electrode and the secondelectrode may be coupled to a cardiac branch of a vagus nerve, with thefirst electrode (e.g., anode) being proximal to the brain relative tothe second electrode, and the second electrode (e.g., cathode) beingproximal to the heart relative to the first electrode.

FIG. 5 is a flow diagram of another method of treating a patient havingepilepsy according to the present disclosure. A sensor is used to sensea cardiac signal and a kinetic signal of the patient (540). In aparticular embodiment, the cardiac sensor may comprise an electrode pairfor sensing an ECG (electrocardiogram) or heart beat signal, and thekinetic signal may comprise a triaxial accelerometer to detect motion ofat least a portion of the patient's body. The method further comprisesanalyzing at least one of the cardiac signal and the kinetic signalusing seizure detection algorithm (550), and the output of the algorithmis used to determine whether at least one of the cardiac signal and thekinetic signal indicate that the patient is having and/or has had anepileptic seizure (560).

If the patient is not having and/or has not had an epileptic seizure,the method comprises applying a first electrical signal to a main trunkof a vagus nerve of the patient using a first electrode, coupled to themain trunk, as a cathode (580). In one embodiment, the first electricalsignal is an open-loop electrical signal having an on-time and off-time.

If the patient is having and/or has had an epileptic seizure, adetermination is made whether the seizure is characterized by anincrease in the patient's heart rate (570). If the seizure is notcharacterized by an increase in the patient's heart rate, the methodcomprises applying the first electrical signal to the main trunk of avagus nerve using the first electrode as a cathode (580). In oneembodiment, the cathode comprises an upper main trunk electrode 125-1and the anode is selected from a cardiac branch electrode 125-2 and alower main trunk electrode 125-3. Conversely, if the seizure ischaracterized by an increase in the patient's heart rate, the methodcomprises applying a second electrical signal to a cardiac branch of avagus nerve of the patient using a second electrode, coupled to thecardiac branch, as a cathode (590). The anode is an upper main trunkelectrode 125-1 or a lower main trunk electrode 125-3. In oneembodiment, the method may comprise suspending the first electrical andapplying the second electrical signal.

The method then continues the sensing of the cardiac and kinetic signalsof the patient (540) and resumes the method as outlined in FIG. 5.

FIG. 6 is a flow diagram of a further method of treating a patienthaving epilepsy according to the present disclosure. The method includesapplying a first, open-loop electrical signal to a main trunk of a vagusnerve (610). The open-loop signal is characterized by an off-time inwhich electrical pulses are applied to the nerve, and an off-time inwhich electrical pulses are not applied to the nerve.

A sensor is used to sense at least one body signal of the patient (620),and a determination is made whether the at least one body signalindicates that the patient is having and/or has had an epileptic seizure(630). If the patient is not having and/or has not had a seizure, themethod continues applying the first, open-loop electrical signal to amain trunk of a vagus nerve (610). If the patient is having and/or hashad an epileptic seizure, a determination is made whether the seizure ischaracterized by an increase in the patient's heart rate (640). In oneembodiment, the increase in heart rate is measured from a baseline heartrate existing prior to the seizure, e.g., a median heart rate for aprior period such as the 300 beats prior to the detection of the seizureevent, or the 5 minutes prior to the detection of the seizure.

If the seizure is not characterized by an increase in the patient'sheart rate, the method comprises applying a second, closed-loopelectrical signal to the main trunk of the vagus nerve 650). In oneembodiment, the second, closed-loop electrical signal is the same signalas the open-loop electrical signal, except that the second signal (asdefined, e.g., by a current intensity, a pulse frequency, a pulse widthand an on-time) is applied at a time different from the programmedtiming of the first electrical signal. For example, if the firstelectrical signal comprises an on-time of 30 seconds and an off-time of5 minutes, but a seizure is detected 1 minute after the end of aprogrammed on-time, the second electrical signal may comprise applying a30 second pulse burst at the same current intensity, frequency, andpulse width as the first signal, but four minutes earlier than wouldhave occurred absent the detected seizure. In another embodiment, thesecond, closed-loop electrical signal is a different signal than thefirst, open-loop electrical signal, and the method may also comprisesuspending the first electrical before applying the second electricalsignal. For example, the second, closed-loop electrical signal maycomprise a higher current intensity, frequency, pulse width and/oron-time than the first, open-loop electrical signal, and may notcomprise an off-time (e.g., the second electrical signal may be appliedfor a predetermined duration independent of the on-time of the first,open-loop electrical signal, such as a fixed duration of 1 minute, ormay continue for as long as the body signal indicates the presence ofthe seizure event).

Returning to FIG. 6, if the seizure is characterized by an increase inthe patient's heart rate, the method comprises applying a third,closed-loop electrical signal to a cardiac branch of a vagus nerve toreduce the patient's heart rate (660). The method may comprisesuspending the first electrical as well as applying the third,closed-loop electrical signal. In one embodiment of the disclosure, eachof the first, open-loop electrical signal, the second, closed-loopelectrical signal, and the third, closed-loop electrical signal areapplied unilaterally (i.e., to vagus nerve structures on the same sideof the body) to the main trunk and cardiac branch of the vagus nerve.For example, the first, open-loop electrical signal and the second,closed-loop electrical signal may be applied to a left main trunk of thepatient's cervical vagus nerve, and the third, closed-loop electricalsignal may be applied to the left cardiac branch of the vagus nerve.Similarly, the first, second and third electrical signals may all beapplied to the right vagus nerve of the patient. In alternativeembodiments, one or more of the first, second and third electricalsignals may be applied bilaterally, i.e., one of the first, second andthird electrical signals is applied to a vagal structure on the oppositeside of the body from the other two signals. For example, in aparticular embodiment the first, open-loop signal and the second,closed-loop signal may be applied to a left main trunk of the patient'scervical vagus nerve, and the third, closed-loop electrical signal maybe applied to a right cardiac branch of the patient's vagus nerve.Because the right cardiac branch modulates the sinoatrial node of thepatient's heart, which is the heart's “natural pacemaker,” the thirdelectrical signal may have more pronounced effect in reducing thepatient's heart rate if applied to the right cardiac branch.

After applying one of the second (650) and third (660) electricalsignals to a vagus nerve of the patient, the method then continuessensing at least one body signal of the patient (620) and resumes themethod as outlined in FIG. 6.

In the methods depicted in FIGS. 4-6, one or more of the parametersdefining the first, second, and third electrical signals (e.g., numberof pulses, pulse frequency, pulse width, On time, Off time, interpulseinterval, number of pulses per burst, or interburst interval, amongothers) can be changed by a healthcare provided using a programmer 150.

FIG. 7 is a flow diagram of a method of treating patients havingseizures accompanied by increased heart rate. In one embodiment,tachycardia is defined as a neurogenic increase in heart rate, that is,an elevation in heart rate that occurs in the absence of motor activityor that if associated with motor activity, the magnitude of the increasein heart rate is larger than that caused by motor activity alone. In oneembodiment, a body signal is acquired (710). The body signal maycomprise one or more body signals that may be altered, changed orinfluenced by an epileptic seizure. As non-limiting examples, the bodysignal may comprise one or more of a cardiac signal such as heart rate,heart rate variability, or EKG complex morphology, a kinetic signal suchas an accelerometer signal, a postural signal or body position signal),blood pressure, blood oxygen concentration, skin resistivity orconductivity, pupil dilation, eye movement, EEG, reaction time or otherbody signals. The body signal may be a real-time signal or a storedsignal for delayed or later analysis. It may be acquired, for example,from a sensor element (e.g., coupled to a processor), from a storagedevice in which the signal data is stored.

The method further comprises determining whether or not the patient ishaving and/or has had a seizure accompanied by an increase in heart rate(720). In one embodiment, the method comprises a seizure detectionalgorithm that analyzes the acquired body signal data and determineswhether or not a seizure has occurred. In a particular embodiment, themethod comprises an algorithm that analyzes one or more of a cardiacsignal, a kinetic signal, a cognitive signal, blood pressure, bloodoxygen concentration, skin resistivity or conductivity, pupil dilation,and eye movement to identify changes in the one or more signals thatindicate a seizure has occurred. The method may comprise an outputsignal or data flag that may be asserted or set when the detectionalgorithm determines from the body signal(s) that the patient is havingand/or has had a seizure.

The method also comprises determining (720) whether or not the seizureis accompanied by an increase in heart rate. In one embodiment, the bodydata signal comprises a heart beat signal that may be analyzed todetermine heart rate. In some embodiments, the heart beat signal may beused by the seizure detection algorithm to determine whether a seizurehas occurred, while in other embodiments seizures are not detected usingheart rate. Regardless of how the seizure is detected, however, themethod of FIG. 7 comprises determining whether a detected seizure eventis accompanied by an increase in heart rate. The increase may bedetermined in a variety of ways, such as by an increase in aninstantaneous heart rate above a reference heart rate (which may be apredetermined interictal value such as 72 beats per minute (bpm), or areal-time measure of central tendency for a time window, such as a 5minute median or moving average heart rate). Additional details aboutidentifying increases in heart rate in the context of epileptic seizuresare provided in U.S. Pat. Nos. 5,928,272, 6,341,236, 6,587,727,6,671,556, 6,961,618, 6,920,357, 7,457,665, as well as U.S. patentapplication Ser. Nos. 12/770,562, 12/771,727, 12/771,783, 12/884,051,12/886,419, 12/896,525, 13/098,262, and 13/288,886, each of which ishereby incorporated by reference in its entirety herein.

If the body data signal does not indicate that the patient is havingand/or has had a seizure accompanied by tachycardia, the methodcomprises applying a first electrical signal to a left vagus nerve. Ifthe body signal does indicate that the patient has experienced a seizureaccompanied by tachycardia, the method comprises applying a secondelectrical signal to a right vagus nerve.

Without being bound by theory, it is believed that stimulation of theright vagus nerve, which enervates the right sinoatrial nerve thatfunctions as the heart's natural pacemaker, will have a more prominenteffect in slowing the heart rate than stimulation of the left vagusnerve. The present disclosure takes advantage of this electricalasymmetry of the left and right vagus nerves to minimize the effect ofVNS on heart rate except where there is a need for acute intervention toslow the heart rate, i.e., when the patient has experienced andepileptic seizure, and the seizure is accompanied by an increase inheart rate. This may result in, for example, stimulation of the leftvagus nerve either when there is no seizure (such as when an open-loopstimulation program off-time has elapsed and the program initiatesstimulation in accordance with a programmed signal on-time), or whenthere is a detected seizure event that is not accompanied by an increasein heart rate (such as absence seizures); and stimulation of the rightvagus nerve when there is a detected seizure event accompanied by aheart rate increase. In one embodiment, a programmed, open-loopelectrical signal is applied to the left vagus nerve except when analgorithm analyzing the acquired body signal detects a seizureaccompanied by a heart rate increase. In response to such a detection, aclosed-loop electrical signal is applied to the right vagus nerve toslow the patient's (increased) heart rate. In some embodiments, theresponse to detecting a seizure accompanied by a heart rate increase mayalso include interrupting the application of the programmed-open-loopelectrical signal to the left vagus nerve. The interrupted open-loopstimulation of the left vagus nerve may be resumed either when theseizure ends or the heart rate returns to a desired, lower heart rate.

In an additional embodiment of the disclosure, electrode pairs may beapplied to each of the left and right vagus nerves of the patient, andused depending upon whether or not seizures accompanied by cardiacchanges such as tachycardia are detected.

FIG. 8 is a flowchart depiction of a method of treating patients havingseizures accompanied by a relative or absolute decrease in heart rate(i.e., a bradycardia episode). Epileptic seizures originating fromcertain brain regions may trigger decreases in heart rate of a magnitudesufficient to cause loss of consciousness and of postural tone (i.e.,syncope). In some subjects the cerebral ischemia associated with thebradycardia may in turn lead to convulsions (i.e., convulsive syncope).If bradycardia-inducing seizures are not controllable by medications,the current treatment is implantation of a demand cardiac pacemaker. Inone embodiment of the present disclosure, ictal bradycardia may betreated by preventing vagal nerve impulses from reaching the heart,either by preventing impulses traveling through all fiber typescontained in the trunk of the nerve or in one of its branches, or byonly blocking impulses within a certain fiber type. In anotherembodiment, the degree of the nerve impulse blocking within a vagusnerve may be determined based upon the magnitude of bradycardia (e.g.,the larger the bradycardia change from the pre-existing baseline heartrate, the larger the magnitude of the block) so as to preventtachycardia from occurring.

In one embodiment, a body signal is acquired (810). The body signal maycomprise one or more body signals that may be altered, changed orinfluenced by an epileptic seizure. Changes in the body signal may beused to detect the onset or impending onset of seizures. As noted withreference to FIG. 7, the body signal may comprise one or more measurederived from a cardiac signal (e.g., heart rate, heart rate variability,change in EKG morphology), a kinetic signal (e.g., an accelerometer,force of muscle contraction, posture or body position signal), bloodpressure, blood oxygen concentration, skin resistivity/conductivity,pupil dilation, eye movement, or other body signals. The body signal maybe a real-time signal, a near-real-time signal, or a non-real-timesignal, although in preferred embodiments, the signal is a real-timesignal or a near-real-time signal. The signal may be acquired from asensor element (e.g., coupled to a processor) or from a storage device.

Referring again to FIG. 8, the method further comprises determiningwhether or not the patient is having and/or has had a seizure that isaccompanied by a decrease in heart rate (820). In one embodiment, themethod comprises using a seizure detection algorithm using one or moreof a cardiac, kinetic, neurologic, endocrine, metabolic or tissue stressmarker to detect seizures, and to determine if the seizure is associatedwith a decrease in heart rate. In a particular embodiment, analgorithm—which may comprise software and/or firmware running in aprocessor in a medical device—analyzes one or more of a cardiac signal,a kinetic signal, blood pressure, blood oxygen concentration, skinresistivity or conductivity, pupil dilation, and eye movement toidentify changes in the one or more signals that indicate the occurrenceof an epileptic seizure. Such changes may be identified by determiningone or more indices from the foregoing signals, such as a cardiac index(e.g., a heart rate), a kinetic index (e.g., a kinetic level or motiontype, a magnitude of an acceleration or force, or other indices that maybe calculated from an accelerometer signal). The method may includeproviding an output signal or setting a data flag when the detectionalgorithm determines from the body signal(s) that the patient is havingand/or has had a seizure. In a preferred embodiment, the seizuredetection occurs in real time and the output signal or data flag is setimmediately upon detection of the seizure.

Once it is determined that the patient is having and/or has had aseizure, the method also comprises determining if the seizure isaccompanied by a decrease in heart rate. In one embodiment, the acquiredbody data signal (810) comprises a heart beat signal that may beanalyzed to determine heart rate. In some embodiments, the acquiredheart beat signal may be used by the seizure detection algorithm todetermine whether a seizure has occurred, while in other embodimentsseizures are determined without regard to the patient's heart rate.Regardless of how the seizure is determined, the method of FIG. 8comprises determining whether a detected seizure event is accompanied bya decrease in heart rate (820). The decrease in heart rate may bedetermined in a variety of ways, such as by a decrease in aninstantaneous heart rate below a reference heart rate value (which maybe a predetermined interictal value such as 72 beats per minute (bpm),or a real-time measure of central tendency for a time window ornumber-of-beats window (e.g., a 5 minute median or moving average heartrate, or a media heart rate for a window selected from 3-300 beats suchas a 5, 10, or 300 beat window)). Additional details about identifyingdecreases in heart rate in the context of epileptic seizures areprovided in U.S. patent application Ser. Nos. 12/770,562, 12/771,727,12/771,783, 12/884,051, 12/886,419, 13/091,033, each of which is herebyincorporated by reference in its entirety herein.

In one embodiment, if the acquired body data signal does not indicatethat the patient is having and/or has had a seizure accompanied by a HRdecrease, the method comprises applying a first electrical signal to avagus nerve (840), wherein the first electrical signal is sufficient togenerate exogenous action potentials in fibers of the vagus nerve. Thesecond electrical signal is a therapeutic electrical signal to treat theseizure. It may be applied to either the left or right vagus nerves, orboth. The first electrical signal may be a signal defined by, amongother parameters, an on-time during which electrical pulses are appliedto the nerve, and an off-time during which no pulses are applied to thenerve. In some embodiments, the on-time may be determined by theduration and intensity of the change in heart rate, while in otherembodiments it may be pre-programmed. Cathode(s) and anode(s) may beplaced on the nerve trunks or branches to maximize flow of exogenouslygenerated nerve impulses in a caudal direction (for control of heartrate changes) and a cephalic direction for seizure treatment.

If the body signal indicates that the patient is having and/or has had aseizure accompanied by a decrease in heart rate, the method comprisesapplying an action to decrease vagal/parasympathetic tone. In oneembodiment, the method comprises blocking the passage of impulsesthrough at least one of a vagus nerve trunk or branch. This may beaccomplished by applying one or more of a second electrical signal(e.g., a high frequency electrical signal), a thermal signal (e.g.,cooling), a chemical signal (e.g., applying a local anesthetic), and/ora mechanical signal (e.g., applying pressure or a vibration) to a vagusnerve of the patient (830). In another embodiment, the method comprisesdelivering at least one of an anti-cholinergic drug or asympatho-mimetic drug.

As used herein, blocking vagus nerve activity means blocking intrinsicor native vagal activity (i.e., blocking action potentials notartificially or exogenously induced by an electrical signal generated bya device). The blocking signal may block the conduction of actionpotentials in all or at least some portion or fraction of the axons of avagus nerve. In general, such blocking signals are incapable of inducingexogenous action potentials in the axons of the vagus nerve. In oneembodiment, the blocking signal may comprise a high frequency, pulsedelectrical signal, the pulse frequency being sufficient to inhibitpropagation of at least some action potentials in vagus nerve fibers.The electrical signal may comprise a signal in excess of 300 Hz, orother frequency, so long as the frequency and other stimulation signalparameters (such as pulse width and pulse current or voltage) provide asignal capable of inhibiting some or all of the action potentialspropagating along fibers of the vagus nerve. In alternative embodiments,the electrical signal may comprise generating unidirectional actionpotentials for collision blocking of endogenous action potentials.

High frequency vagus nerve stimulation (or other blocking signals suchas collision blocking) may inhibit pathological vagus nerve activityassociated with the seizure that may be acting to slow the patient'sheart rate. By providing such stimulation only when the patientexperiences a seizure accompanied by a reduced heart rate (e.g.,bradycardia), a therapy may be provided that acts to maintain thepatient's heart rate when the patient experiences a seizure involvingexcessive vagal activity—and consequent undesired slowing of—the heart.In one embodiment, the blocking electrical signal (830) is provided to aright vagus nerve. Without being bound by theory, because the rightvagus nerve innervates the right sinoatrial node that functions as theheart's natural pacemaker, it is believed that right-side VNS will havea more significant effect upon the heart rate than stimulation of theleft vagus nerve. In alternative embodiments, the blocking signal may beapplied to the left vagus nerve, to both the right and left vagusnerves, or to one or both of the left and right cardiac branches of thevagus nerves.

In one embodiment, the method comprises applying a first electricalsignal that may be a conventional vagus nerve stimulation signal definedby a plurality of parameters (e.g., a pulse width, a current magnitude,a pulse frequency, an on-time and an off-time). A seizure detectionalgorithm (e.g., using one or more of a cardiac, kinetic, metabolic,EEG, or other body signal) may be used to detect seizures, and thepatient's heart rate may be determined proximate the seizure detectionto determine if the seizure is accompanied by a decrease in thepatient's heart rate. If the seizure is accompanied by a slowing of thepatient's heart rate, the first electrical signal may be suspended, anda second electrical signal may be applied to slow the patient's heartrate. The method may further include sensing the patient's heart rateduring or after application of the second electrical signal. In oneembodiment, the second electrical signal may be modified (e.g., bychanging current magnitude, pulse width, or pulse frequency), orsuspended (and possibly resumed) to maintain the patient's heart ratebetween an upper heart rate threshold and a lower heart rate threshold.In some embodiments, the upper and lower heart rate thresholds may bedynamically set (e.g., as no more than 5 bpm above or below the baselineHR prior to the seizure detection).

FIG. 9 is a flow diagram of a method of treating a patient with epilepsyby providing closed-loop vagus nerve intervention (e.g., stimulation orblockage of impulse conduction) to maintain the patient's heart ratewithin a range that is both safe and also commensurate with the activitytype or level and state of the patient (e.g., as determined from akinetic signal from a sensing element such as a triaxial accelerometeror by measuring oxygen consumption). In one embodiment, the methodcomprises providing vagus nerve stimulation in response to determiningthat a heart rate is incommensurate with the kinetic signal of thepatient, to restore cardiac function to a rate that is commensurate withthe patient's kinetic signal. In one embodiment, the stimulation maycomprise stimulating a right vagus nerve to slow the patient's heartrate to a level that is safe and/or commensurate with activity level. Inanother embodiment, the stimulation may comprise providing a blockingsignal to increase a slow heart rate to a rate that is safe and/orcommensurate with the activity level. Pharmacologic compounds (e.g.,drugs) with sympathetic or parasympathetic effects (e.g., enhancing orblocking sympathetic or parasympathetic activity) may be used to restoreheart rate to a rate commensurate with kinetic activity of the patientin still other embodiments. In one embodiment, the method involvesdetermining a heart rate and one or more kinetic or metabolic (e.g.,oxygen consumption) indices for the patient (910). Heart rate may bedetermined from an acquired cardiac signal (e.g., from a sensor orstored data). Kinetic and/or metabolic indices may likewise bedetermined from a kinetic sensor (e.g., an accelerometer, a positionalsensor, a GPS device coupled to a clock, or a postural sensor), ametabolic sensor, or from stored data. Sensor data may be subjected toone or more operations such as amplifying, filtering, A/D conversion,and/or other pre-processing and processing operations to enabledetermination of heart rate (and in some embodiments other cardiacindices such as heart rate variability) and kinetic indices.

The activity level of the patient may be determined from multiplekinetic indications such as an activity level, a type of activity, aposture, a body position, a trunk or limb acceleration or force, or aduration of one of the foregoing, and may be adapted or modified as afunction of age, gender, body mass index, fitness level or time of dayor other indices of the patient's condition or environment. For example,the kinetic signal may be processed to provide indices that indicatemoderate ambulatory motion for an upright patient, vigorous physicalexercise (in which the patient may be upright as in running or in aprone position as in some calisthenics exercises), a fall (e.g.,associated with a seizure), reclining, resting or sleeping, among otheractivity levels and kinetic states.

The one or more kinetic indices may then be used to determine (e.g., byretrieving stored data from a lookup table or by calculation using analgorithm) one or more heart rate ranges or values that would becommensurate with the kinetic activity and/or kinetic state, duration,time of day, etc. associated with the indices. In some embodiments,heart rate ranges may be established for particular levels or types ofactivity (e.g., running, walking), that may be adaptively adjusteddepending upon various factors such as the duration of the activity, thepatient's fitness level, the time of day, a level of fatigue, anenvironmental temperature, etc. A commensurate heart rate is one that iswithin expected ranges or values for the person's effort, and forfactors inherent to the patient and the environment.

Returning to FIG. 9, the determined heart rate may be compared to therange(s)/value(s) identified as commensurate with the kinetic indices(920) at a given time point. If the actual heart rate of the patient iswithin the expected/commensurate range or value associated with thekinetic or metabolic indices at the time point, or is within a specifiedproximity of a particular range or value, no action may be taken, andthe method may involve continuing to analyze the patient's cardiac andkinetic signals or metabolic signals. On the other hand, if the heartrate is outside the expected value or range of values for the kinetic ormetabolic indices for that time point, then the heart rate is notcommensurate with the kinetic signal of the patient, and a therapy maybe provided to the patient by applying one of an electrical, thermal,mechanical or chemical signal to a vagus nerve of the patient (930) oradministering to the patient (e.g., intravenously, through mucosae) adrug with cholinergic or anti-cholinergic or adrenergic actions,depending on the case or situation. In one embodiment, the method maycomprise applying the signal to a main trunk of a vagus nerve of thepatient, and in another embodiment, the signal may be applied to acardiac branch of a vagus nerve.

In one embodiment, the heart rate of the patient may be higher than avalue commensurate with the activity level or kinetic indices of thepatient. In this case, the patient is having relative tachycardia. Wherethis is the case, as previously noted, vagus nerve stimulation may beapplied to one or more of a right cardiac branch, left cardiac branch,or right main trunk of the patient's vagus nerve to reduce the patient'sheart rate to a rate that is commensurate with the activity level.Embodiments of the disclosure may be used to treat epileptic seizuresassociated with tachycardia, and other medical conditions associatedwith tachycardia given the patient's activity level. Therapies (e.g.,electrical, chemical, mechanical, thermal) delivered to a patient viathe vagus nerves may be employed for tachyarrythmias, angina pectoris orpain in regions innervated by a vagus nerve.

In another embodiment, the patient's heart rate may be lower than avalue commensurate with the patient's activity level or kinetic indices,that is, the patient is having relative or absolute bradycardia. Highfrequency (>>300 Hz) electrical pulses may be applied to the left orright vagus nerves (e.g., a main trunk of the right and/or left vagusnerves or to their cardiac branches) to block propagation oftransmission of nerve impulses through their fibers. High-frequency VNSmay be applied to block impulses traveling to the heart to abateneurogenic, cardiogenic or iatrogenic bradycardia, or to minimize thecumulative effects on the heart's conduction system and myocardium ofepileptic seizures, especially in status epilepticus. Selective blockageof impulses traveling through a vagus nerve to the heart may beaccomplished with electrical stimulation to treat adverse cardiaceffects associated with disorders such as epilepsy, depression, diabetesor obesity. By blocking vagus nerve conduction to the heart, when thepatient's heart rate is incommensurate with the activity level orkinetic indices, a therapy may be provided to revert the change in heartrate (whether the change involves bradycardia or tachycardia). In oneembodiment, an electrical signal generator may be used to apply a firsttherapy signal to a vagus nerve of the patient, and an electrical signalgenerator (which may be the same or a different electrical signalgenerator) may apply a vagus nerve conduction blocking electrical signalto a vagus nerve (e.g., a cardiac branch of the vagus nerve) to blockcardiac effects that would result from the first electrical signal,absent the vagus nerve conduction blocking electrical signal.

Referring again to FIG. 9, the method may comprise determining thepatient's heart rate in response the therapy to determine whether theheart rate has been restored to a rate that is with commensurate withthe patient's activity level/kinetic index (940). If not, then thetherapy (e.g., VNS to reduce or increase heart rate to an appropriatevalue) may be continued, with or without parameter modification, orre-initiated after a delay period or confirmation period.

If the heart rate has returned to a range/value commensurate with theactivity level of the patient, the method may, in some embodiments,further involve determining whether or not an adverse event has occurred(950). Adverse events may include, without limitation, side effects suchas voice alteration, pain, difficulty breathing or other respiratoryeffects, adverse cardiac effects such as bradycardia (following adetermination of relative tachycardia in step 920), tachycardia(following a determination of bradycardia in step 920), and alterationin blood pressure or gastro-intestinal activity.

If an adverse event has occurred, the method may involve changing one ormore stimulation parameters to eliminate, reduce or ameliorate theadverse event (955). If no adverse event has occurred, the method maycomprise continuing to apply a signal the vagus nerve until apredetermined signal application duration has been reached (960), atwhich time the signal application may be stopped (970). The method mayfurther comprise determining, after the therapy has been stopped, if thepatient's heart rate remains incommensurate with the patient's activitylevel or type (980), in which case the signal application may be resumedor other appropriate action may be taken (e.g., local or remote alarmsor alerts, notification of caregivers/healthcare providers, etc.). Ifthe heart rate has returned to a value that is commensurate orappropriate for the patient's activity level, the signal application maybe discontinued (990).

FIG. 10 is a flow diagram of a method of treating a patient to withepilepsy by providing closed-loop vagus nerve stimulation to treatrelative tachycardia or relative bradycardia by restoring the patient'sheart rate to a rate that is commensurate with the activity type orlevel of the patient (e.g., as determined from a kinetic signal from asensing element such as a triaxial accelerometer or by measuring oxygenconsumption). In one embodiment, the method comprises identifyinginstances of relative tachycardia or relative bradycardia and respondingwith negative or positive chronotropic actions to restore the heart rateto a level commensurate with the patient's activity type or level.

In one embodiment, the method involves determining a heart rate and anactivity type or level for the patient (1010). The patient's heart ratemay be determined from an acquired cardiac signal or from stored data.The activity level or type of the patient may be determined from one ormore sensor or from stored data. Sensors may include, for example,accelerometers, positional sensors, GPS devices coupled to a clock,postural sensors, and metabolic sensors. Sensor data may be subject toconventional signal processing, and may in addition be adapted ormodified as a function of age, gender, body mass index, fitness level ortime of day or other indices of the patient's condition or environment.

The patient's activity type or level may then be used to determine oneor more heart rate ranges or values that are commensurate with theactivity type or level (1020). In some embodiments, heart rate rangesmay be established for particular levels or types of activity (e.g.,running, walking), that may be adaptively adjusted depending uponvarious factors such as the duration of the activity, the patient'sfitness level, the time of day, a level of fatigue, an environmentaltemperature, etc. A commensurate heart rate is one that is withinexpected ranges or values for the person's effort, and for factorsinherent to the patient and the environment.

If the heart rate is commensurate with the activity level, in oneembodiment no action may be taken, and the method may involve continuingto analyze the patient's cardiac and activity. On the other hand, if theheart rate is outside the identified value or range of valuesappropriate for the patient's activity type or level then the heart rateis not commensurate with the kinetic signal of the patient. Where thisis the case, the method may further comprise determining whether thepatient is experiencing relative tachycardia or is experiencing relativebradycardia (1030, 1040).

Where the heart rate of the patient is higher than a value commensuratewith the activity level or type, the patient is experiencing relativetachycardia (1030), and the method may comprise initiating a negativechronotropic action (1035) to slow the heart rate to a rate that iscommensurate with the activity level or type. In one embodiment, thismay involve applying stimulation to one or more of a left or right mainvagal trunk or cardiac branch of the patient. In other embodiments, themethod may comprise providing a drug to enhance the parasympathetic toneof the patient. In still other embodiments, the method may comprisereducing the patient's sympathetic tone, such as by applyinghigh-frequency stimulation to a sympathetic nerve trunk or ganglion oradministering an anti-cholinergic drug. Negative chronotropic actionsmay be used to treat epileptic seizures associated with tachycardia, andother medical conditions associated with relative tachycardia given thepatient's activity level.

Where the heart rate of the patient is lower than a value commensuratewith the activity level or type, the patient is experiencing relativebradycardia (1040), and the method may comprise initiating a positivechronotropic action (1045) to increase the heart rate to a rate that iscommensurate with the activity level or type. In one embodiment, thismay involve applying high-frequency (>>300 Hz) electrical stimulation toone or more of a left or right main vagal trunk or cardiac branch of thepatient to reduce the transmission of intrinsic vagus nerve actionpotentials in at least some vagal fibers. In other embodiments, themethod may comprise providing a drug to reduce the parasympathetic toneof the patient. In still other embodiments, the method may compriseincreasing the patient's sympathetic tone, such as by applyingelectrical signals to a sympathetic nerve trunk or ganglion or byadministering a sympatho-mimetic drug. Positive chronotropic actions maybe used to treat epileptic seizures associated with bradycardia, andother medical conditions associated with relative bradycardia given thepatient's activity level.

The method may further comprise, after initiating the negative orpositive chronotropic action, determining whether the patient's heartrate has been restored to a rate that is with commensurate with thepatient's activity level/kinetic index (1050). If not, then the therapy(e.g., VNS to reduce or increase heart rate to an appropriate value) maybe continued, with or without parameter modification, or re-initiatedafter a delay period or confirmation period.

If the heart rate has returned to a range/value commensurate with theactivity level of the patient, the method may, in some embodiments,further involve determining whether or not an adverse event has occurred(1060). Adverse events may include, without limitation, side effectssuch as voice alteration, pain, difficulty breathing or otherrespiratory effects, adverse cardiac effects such as bradycardia(following a determination of relative tachycardia in step 1030), ortachycardia (following a determination of bradycardia in step 1040), andalteration in blood pressure or gastric activity.

If an adverse event has occurred, the method may involve changing one ormore stimulation parameters to eliminate, reduce or ameliorate theadverse event (1070). If no adverse event has occurred, the method maycomprise continuing to stimulate the vagus nerve (or a chemical, thermalor mechanical therapy) until a predetermined stimulation duration hasbeen reached (1075), at which time the stimulation may be stopped(1080). The method may further comprise determining, after the therapyhas been stopped, if the patient's heart rate remains incommensuratewith the patient's activity level or type (1090), in which case thestimulation may be resumed or other appropriate action may be taken(e.g., local or remote alarms or alerts, notification ofcaregivers/healthcare providers, use of other forms of therapy, etc.).If the heart rate has returned to a value that is commensurate orappropriate for the patient's activity level, the stimulation may bediscontinued (1095).

Additional embodiments consistent with the foregoing description andfigures may be made. Non-limiting examples of some such embodiments areprovided in the numbered paragraphs below.

100. A method of controlling a heart rate of an epilepsy patientcomprising:

sensing at least one of a kinetic signal and a metabolic signal of thepatient;

analyzing the at least one of a kinetic and a metabolic signal todetermine at least one of a kinetic index and a metabolic index;

receiving a cardiac signal of the patient;

analyzing the cardiac signal to determine the patient's heart rate;

determining if the patient's heart rate is commensurate with the atleast one of a kinetic index and a metabolic index; and

applying an electrical signal to a vagus nerve of the patient based on adetermination that the patient's heart rate is not commensurate with theat least one of a kinetic signal and a metabolic signal of the patient.

101. The method of numbered paragraph 100, wherein determining at leastone of a kinetic index and a metabolic index comprises determining atleast one of an activity level or an activity type of the patient basedon the at least one of a kinetic index and a metabolic index, and

wherein determining if the patient's heart rate is commensurate with theat least one of a kinetic index and a metabolic index of the patientcomprises determining if the heart rate is commensurate with the atleast one of an activity level or an activity type.102. The method of numbered paragraph 101, wherein determining if thepatient's heart rate is commensurate with the at least one of a kineticindex and a metabolic index comprises determining if the patient's heartrate is above or below a rate that is commensurate with the one or moreof a kinetic index and a metabolic index.

103. A method of treating a patient having epilepsy comprising

sensing at least one body signal of the patient;

determining whether or not the patient is having or has had an epilepticseizure based on the at least one body signal;

sensing a cardiac signal of the patient;

determining whether or not the seizure is associated with a change inthe patient's cardiac signal;

applying a first therapy to a vagus nerve of the patient based on adetermination that the patient is having or has had an epileptic seizurethat is not associated with a change in the patient's cardiac signal,wherein the first therapy is selected from an electrical, chemical,mechanical, or thermal signal; and

applying a second therapy to a vagus nerve of the patient based on adetermination that the patient is having or has had an epileptic seizureassociated with a change in the patient's cardiac signal, wherein thesecond therapy is selected from an electrical, chemical, mechanical(e.g., pressure) or thermal signal.

104. The method of numbered paragraph 103, further comprising applying athird therapy to a vagus nerve of the patient based a determination thatthe patient is not having or has not had an epileptic seizure, whereinthe third therapy is selected from an electrical, chemical, mechanicalor thermal signal.

105. A method of treating a patient having epilepsy comprising:coupling a first set of electrodes to a main trunk of the left vagusnerve of the patient; coupling a second set of electrodes to a maintrunk of the right vagus nerve of the patient; providing an electricalsignal generator coupled to the first electrode set and the secondelectrode set;receiving at least one body data stream;

analyzing the at least one body data stream using a seizure detectionalgorithm to determine whether or not the patient is having and/or hashad an epileptic seizure;

applying a first electrical signal from the electrical signal generatorto the main trunk of the left vagus nerve, based on a determination thatthe patient is having and/or has had an epileptic seizure without aheart rate change; and

applying a second electrical signal from the electrical signal generatorto the main trunk of the right vagus nerve, based on a determinationthat the patient is having or has had an epileptic seizure with a heartrate change.

106. A method of treating a patient having epilepsy comprising:

receiving at least one body data stream;

analyzing the at least one body data stream using a seizure detectionalgorithm to detect whether or not the patient has had an epilepticseizure;

receiving a cardiac signal of the patient;

analyzing the cardiac signal to determine a first cardiac feature;

applying a first electrical signal to a vagus nerve of the patient,based on a determination that the patient has not had an epilepticseizure characterized by a change in the first cardiac feature, whereinthe first electrical signal is not a vagus nerve conduction blockingelectrical signal; and

applying a second electrical signal to a vagus nerve of the patient,based on a determination that the patient has had an epileptic seizurecharacterized by a change in the cardiac feature, wherein the secondelectrical signal is a pulsed electrical signal that blocks actionpotential conduction in the vagus nerve.

107. A method of treating a patient having epilepsy comprising:

receiving at least one body data stream;

analyzing the at least one body data stream using a seizure detectionalgorithm to detect whether or not the patient has had an epilepticseizure;

receiving a cardiac signal of the patient;

analyzing the cardiac signal to determine a first cardiac feature;

applying a first electrical signal to a vagus nerve of the patient,based on a determination that the patient has not had an epilepticseizure characterized by a change in the first cardiac feature, whereinthe first electrical signal is a pulsed electrical signal that blocksaction potential conduction in the vagus nerve; and

applying a second electrical signal to a vagus nerve of the patient,based on a determination that the patient has had an epileptic seizurecharacterized by a change in the cardiac feature, wherein the secondelectrical signal is not a vagus nerve conduction blocking electricalsignal.

In FIG. 11, a graph of heart rate versus time is shown, according to oneembodiment. A first graph 1100 includes a y-axis 1102 which representsheart rate where the heart rate goes from a zero value to an Nth value(e.g., 200 heart beats, etc.). Further, the first graph 1100 includes anx-axis 1104 which represents time from 1 minute to Nth minutes (and/or0.001 seconds to Nth seconds). In this example, a first heart rateversus time line 1106 for the patient is shown. In this example, thepatient's heart rate goes from 80 heart beats per minute to 118 heartbeats per minute with a first rise 1108A and a first run 1108B during afirst event 1108C. In addition, the patient's heart rate goes from 70heart beats per minute to 122 heart beats per minute during a secondevent 1108D which has a first percentage change 1110 associated with thesecond event 1108D. Further, the patient's heart rate goes from 70 beatsper minute to 113 beats per minute during an nth event 1108E whichsurpasses a first threshold amount 1112, and/or a second thresholdamount 1114, and/or an Nth threshold amount 1116. In one example, onlythe Nth threshold amount 1116 needs to be reached to trigger a therapyand/or an alert. In another example, only the second threshold amount1114 needs to be reached to trigger a therapy and/or an alert. Inanother example, only the first threshold 1112 needs to be reached totrigger a therapy and/or an alert. In another example, both the Nththreshold 1116 and the second threshold 1114 need to reached to triggera therapy and/or an alert. In another example, all of the Nth threshold1116, the second threshold 1114 and the first threshold 1112 need toreached to trigger a therapy and/or an alert. In one example, only theNth threshold amount 1116 needs to be reached during a specific timeperiod to trigger a therapy and/or an alert. In another example, onlythe second threshold amount 1114 needs to be reached during a specifictime period to trigger a therapy and/or an alert. In another example,only the first threshold 1112 needs to be reached during a specific timeperiod to trigger a therapy and/or an alert. In another example, boththe Nth threshold 1116 and the second threshold 1114 need to reachedduring a specific time period to trigger a therapy and/or an alert. Inanother example, all of the Nth threshold 1116, the second threshold1114 and the first threshold 1112 need to reached during a specific timeperiod to trigger a therapy and/or an alert. In these examples, one ormore triggering events may occur based on a determination of the riseand run of a change in heart rate, a percentage change in heart rate, athreshold amount being reached or exceeded (or within any percentage ofthe threshold), and/or any combination thereof. A triggering event mayinitiate one or more actions to increase and/or decrease the patient'sheart rate. For example, if the patient's heart rate is increasing whichdetermines the triggering event, then the system, device, and/or methodmay initiate one or more actions to decrease the heart rate of thepatient to help reduce, dampen, eliminate, and/or buffer the increase inthe patient's heart rate. Further, the system, device, and/or method mayoscillate between decreasing the patient's heart rate and increasing thepatient's heart rate depending on any changes to the patient's heartrate. For example, the system, device, and/or method may initiate one ormore actions to decrease a patient's heart rate based on the patient'sheart rate going from 80 heart beats per minute to 130 heart beats perminute which results in the patient's heart rate falling from 130 heartbeats per minute to 65 heart beats per minute in a first time period.Based on the change in the heart rate from 130 heart beats per minute to65 heart beats per minute in the first time period, the system, device,and/or method may initiate one or more actions to increase the patient'sheart rate and/or stabilize the patient's heart rate. In anotherexample, the system, method, and/or device may stop and/or modify anyinitiated action based on one or more feedback signals. In addition, oneor more warnings may be transmitted to the patient, a caregiver, adoctor, a medical professional, and/or logged.

In FIG. 12, another graph of heart rate versus time is shown, accordingto one embodiment. A second graph 1200 illustrating a second heart rateversus time line 1202 for the patient is shown. In this example, thepatient's heart rate goes from 80 heart beats per minute to 120 heartbeats per minute which creates a first system alert event 1204 (e.g.,A1). Further, the system, device, and/or method initiates a firsttherapy 1206 (e.g., X1) based on the first system alert event 1204. Inaddition, a second system alert event 1208 (e.g., A2) occurs and asecond therapy 1210 (e.g., X2) is initiated based on the second systemalert event 1208. In addition, a third system alert event 1212 (e.g.,A3) occurs and a third therapy (e.g., X3) 1214 is initiated based on thethird system alert event 1212 (e.g., A3). In addition, a fourth systemalert event 1216 (e.g., A4) occurs and a fourth therapy 1218 (e.g., X4)is initiated based on the fourth system alert event 1216 (e.g., A3).Further, a fifth therapy 1220 (e.g., X5) is initiated based on theeffects of the fourth therapy 1218 (e.g., X4). In addition, a fifthsystem alert event 1222 (e.g., A5) occurs and a sixth therapy (e.g., X6)1224 is initiated based on the fifth system alert event 1222 (e.g., A5).In addition, a sixth system alert event 1226 (e.g., A6) occurs and aseventh therapy (e.g., X7) 1228 is initiated based on the sixth systemalert event 1226 (e.g., A6). In addition, a seventh system alert event1230 (e.g., A7) occurs and an eighth therapy (e.g., X8) 1232 isinitiated based on the seventh system alert event 1230 (e.g., A7). Inaddition, a first stop stimulation event 1234 (e.g., B1) occurs whichturns off all therapies and/or system alerts may occur when the heartrate returns to the approximate starting heart rate and/or a targetvalue. In these examples shown with FIG. 12, a rise over run heart ratecalculation was completed to determine the one or more system alerts.However, it should be noted that any calculation (e.g., % increase, %decrease, etc. can be utilized). Further, all systems alerts and/ortherapies may occur as independent events and/or examples. For example,the seventh system alert may be the first system alert in a specificexample. In other words, no other events and/or therapies occurredbefore the seventh system alert. Therefore, the seventh system alertbecomes the first system alert. In addition, one or more warnings may betransmitted to the patient, a caregiver, a doctor, a medicalprofessional, and/or logged. In addition, there may be up to an Nthalerts, an Nth stop stimulation (and/or therapy) event, and an Nththerapy in any of the examples disclosed in this document.

In FIG. 13, another graph of heart rate versus time is shown, accordingto one embodiment. A third graph 1300 illustrating a third heart rateversus time line 1302 for the patient is shown. In this example, thepatient's heart rate goes from 80 heart beats per minute to 116 heartbeats per minute which creates a first system alert event 1304 (e.g.,A1). Further, the system, device, and/or method initiates a firsttherapy 1306 (e.g., X1) based on the first system alert event 1304. Inaddition, a first stop stimulation event 1308 (e.g., B1) occurs whichturns off all therapies and/or system alerts occurs when the heart ratereturns to the approximate starting heart rate and/or a target value.Further, the patient's heart rate goes from 80 heart beats per minute to123 heart beats per minute which creates a second system alert event1310 (e.g., A2). Further, the system, device, and/or method initiates asecond therapy 1312 (e.g., X2) based on the second system alert event1310. In addition, a second stop stimulation event 1314 (e.g., B2)occurs which turns off all therapies and/or system alerts occurs whenthe heart rate returns to the approximate starting heart rate and/or atarget value. In these examples shown with FIG. 13, a percentage changein heart rate calculation was completed to determine the one or moresystem alerts. However, it should be noted that any calculation (e.g.,rise over run, etc. can be utilized). Further, all systems alerts and/ortherapies may occur as independent events and/or examples. For example,the second system alert may be the first system alert in a specificexample. In other words, no other events and/or therapies occurredbefore the second system alert. Therefore, the second system alertbecomes the first system alert. In addition, one or more warnings may betransmitted to the patient, a caregiver, a doctor, a medicalprofessional, and/or logged.

In FIG. 14, another graph of heart rate versus time is shown, accordingto one embodiment. A fourth graph 1400 illustrating a fourth heart rateversus time line 1402 for the patient is shown. In this example, thepatient's heart rate goes from 80 heart beats per minute to 120 heartbeats per minute which creates a first system alert event 1404 (e.g.,A1) because the 120 heart beats per minutes meets or exceeds a firstthreshold value 1416 (e.g., 115 heart beats per minute). In thisexample, a second system alert event 1406 (e.g., A2) is created becausethe heart beats of the patient meets or exceeds the first thresholdvalue 1416 (e.g., 115 heart beats per minute). Further, the system,device, and/or method initiates a first therapy 1408 (e.g., X1) based onthe first system alert event 1404 and the second system alert event 1406occurring. The first system alert event 1404 and the second system alertevent 1406 may be time dependent. For example, the first system alertevent 1404 and the second system alert event 1406 may have to occurwithin a first time period for the initiation of the first therapy 1408.In another example, the first system alert event 1404 and the secondsystem alert event 1406 may not be time dependent. Further, a thirdsystem alert event 1410 (e.g., A3) is created because the heart beats ofthe patient meets or exceeds (and/or within a specific rate of thethreshold—in this example within 5 percent—heart rate is 110) the firstthreshold value 1416 (e.g., 115 heart beats per minute). Further, thesystem, device, and/or method initiates a second therapy 1412 (e.g., X2)based on the first system alert event 1404, the second system alertevent 1406, and/or the third system event occurring. It should be notedthat the second therapy 1412 has a time delay factor utilized with thesecond therapy 1412. In another example, no time delay is utilized. Inaddition, one or more time delays can be used with any therapy, anywarning, and/or any alert in this document. The first system alert event1404, the second system alert event 1406, and the third system alertevent 1410 may be time dependent. For example, the first system alertevent 1404, the second system alert event 1406, and the third systemalert event 1410 may have to occur within a first time period for theinitiation of the second therapy 1412. In another example, the firstsystem alert event 1404, the second system alert event 1406, and thethird system alert event 1410 may not be time dependent. Further, afirst stop stimulation event 1414 (e.g., B1) occurs which turns off alltherapies and/or system alerts occurs when the heart rate returns to theapproximate starting heart rate and/or a target value. Further, allsystems alerts and/or therapies may occur as independent events and/orexamples. For example, the third system alert may be the first systemalert in a specific example. In other words, no other events and/ortherapies occurred before the third system alert. Therefore, the thirdsystem alert becomes the first system alert. In addition, one or morewarnings may be transmitted to the patient, a caregiver, a doctor, amedical professional, and/or logged.

In FIG. 15, another graph of heart rate versus time is shown, accordingto one embodiment. A fifth graph 1500 illustrating a fifth heart rateversus time line 1502 for the patient is shown. In this example, thepatient's heart rate goes from 80 heart beats per minute to 40 heartbeats per minute which creates a first system alert event 1504 (e.g.,A1) because the 40 heart beats per minutes meets or exceeds a firstthreshold value 1520 (e.g., 50 heart beats per minute). It should benoted that no alert was generated when the heart rate fell to 52 heartbeats per minute because 52 heart beats per minute is above thethreshold value of 50 heart beats per minute. Further, the system,device, and/or method initiates a first therapy 1506 (e.g., X1) based onthe first system alert event 1504 occurring. Further, the patient'sheart rate goes from 80 heart beats per minute to 50 heart beats perminute which creates a second system alert event 1508 (e.g., A2) becausethe 50 heart beats per minutes meets or exceeds the first thresholdvalue 1520 (e.g., 50 heart beats per minute). Further, the system,device, and/or method initiates a second therapy 1510 (e.g., X2) basedon the second system alert event 1508 occurring. Further, a first stopstimulation event 1512 (e.g., B1) occurs which turns off all therapiesand/or system alerts occurs when the heart rate returns to theapproximate starting heart rate and/or a target value. In addition, thepatient's heart rate goes from 80 heart beats per minute to 45 heartbeats per minute which creates an nth system alert event 1514 (e.g., A3)because the 45 heart beats per minutes meets or exceeds the firstthreshold value 1520 (e.g., 50 heart beats per minute). Further, thesystem, device, and/or method initiates an Nth therapy 1516 (e.g., X3)based on the nth system alert event 1514 occurring. Further, an nth stopstimulation event 1518 (e.g., B2) occurs which turns off all therapiesand/or system alerts occurs when the heart rate returns to theapproximate starting heart rate and/or a target value. Further, allsystems alerts and/or therapies may occur as independent events and/orexamples. For example, nth system alert event 1514 alert may be thefirst system alert in a specific example. In other words, no otherevents and/or therapies occurred before nth system alert event 1514.Therefore, nth system alert event 1514 becomes the first system alert.In addition, one or more warnings may be transmitted to the patient, acaregiver, a doctor, a medical professional, and/or logged.

In regards to FIGS. 11-15 as related to this disclosure, the systems,devices, and/or methods may use a base line heart rate for the patient(e.g., a specific patient Bob, a general patient John Doe with a firsthealth condition, a first age, etc.) over a first time period (e.g. oneweek, one month, one year, etc.), 50 percentile of all measured heartrates, an average of all heart rates, and/or any other method ofdetermine a baseline heart rate. Further, the threshold level may bedetermined based on being the 40 percentile of the baseline, 39percentile of the baseline, 38 percentile of the baseline, . . . , 10percentile of the baseline, . . . , etc. In addition, the thresholdlevel may be determined based on being the 75 percentile of thebaseline, 76 percentile of the baseline, 77 percentile of the baseline,. . . , 90 percentile of the baseline, . . . , 99 percentile of thebaseline, . . . , etc. In one example, the threshold value may be the 75percentile of every recorded heart rate data. In another example, theoscillation does not matter whether the heart rate change is in anincreasing direction or a decreasing direction. In various examples, thesystems, devices, and/or method may reduce an amplitude of change (e.g.,damping the change in heart rate) to enhance system performance and/orto reduce side effects. In addition, the determination of one or moreside effects may initiate a reduction in therapy, a stoppage of therapy,a modification of therapy (e.g., changing a therapy that reduces heartrate to another therapy that increases heart rate), one or morewarnings, and/or one or more logging of data.

In FIG. 16, a flowchart of a therapy procedure is shown, according toone embodiment. A method 1600 includes obtaining one or more data pointsand/or characteristics relating to heart rate of a patient (step 1602).The method 1600 may also include determining a monitored value based onethe obtained one or more data points and/or characteristics relating tothe heart rate (step 1604). The method 1600 may further compare themonitored value to one or more threshold values (step 1606). The method1600 may via one or more processors (of a medical device(s) and/ormedical device system) determine whether a triggering event has occurred(step 1608). If no triggering event has occurred, then the method 1600moves back to step 1602. If a triggering event has occurred, then themethod 1600 may determine via one or more processors (of a medicaldevice(s) and/or medical device system) whether an action whichincreases heart rate should be implemented (step 1610). If an actionwhich increases heart rate should be implemented, then the method 1600may increase a sympathetic tone via one or more actions and/or decreasea parasympathetic tone via one or more actions and/or implement anotheraction which increases heart rate (step 1612). After the implements ofone or more actions, the method 1600 returns to step 1602. If an actionwhich increases heart rate should not be implemented, then the method1600 may determine via one or more processors (of a medical device(s)and/or medical device system) whether an action which decreases heartrate should be implemented (step 1614). If an action which decreasesheart rate should be implemented, then the method 1600 may decrease asympathetic tone via one or more actions and/or increase aparasympathetic tone via one or more actions and/or implement anotheraction which decreases heart rate (step 1616). After the implements ofone or more actions, the method 1600 returns to step 1602.

In one embodiment, a system for treating a medical condition in apatient includes: a sensor for sensing at least one body data stream; aheart rate unit capable of determining a heart rate of the patient basedon the at least one body data stream; and a logic unit configured viaone or more processors to compare a monitored value which is determinedbased on one or more data points relating to the heart rate to one ormore threshold values, the logic unit further configured to determine atriggering event based on the comparison. Further, the one or moreprocessors may initiate one or more actions to change the heart rate ofthe patient based on the determination of the triggering event.

In another example, the system includes at least one electrode coupledto a vagus nerve of the patient and a programmable electrical signalgenerator. In another example, the one or more processors may increase asympathetic tone to increase the heart rate of the patient. In anotherexample, the one or more processors may decrease a parasympathetic toneto increase the heart rate of the patient. In another example, the oneor more processors may decrease a sympathetic tone to decrease the heartrate of the patient. In another example, the one or more processors mayincrease a parasympathetic tone to decrease the heart rate of thepatient. In another example, the system includes a seizure detectionunit which analyzes the at least one body data stream to determine anepileptic seizure status. In another example, the system includes atleast one electrode coupled to a vagus nerve of the patient and aprogrammable electrical signal generator. Further, the one or moreprocessors may apply an electrical signal to the vagus nerve of thepatient based on a determination that a seizure is characterized by adecrease in the heart rate of the patient where the electrical signal isapplied to block action potential conduction on the vagus nerve.

In another embodiment, a system for treating a medical condition in apatient, includes: a sensor for sensing at least one body data stream;at least one electrode coupled to a vagus nerve of the patient; aprogrammable electrical signal generator; a heart rate unit capable ofdetermining a heart rate of the patient based on the at least one bodydata stream; and a logic unit configured via one or more processors tocompare a monitored value which is determined based on one or more datapoints relating to the heart rate to one or more threshold values, thelogic unit further configured to determine a triggering event based onthe comparison. Further, the one or more processors may initiate one ormore actions to change the heart rate of the patient based on thedetermination of the triggering event.

In another example, the one or more processors may increase asympathetic tone to increase the heart rate of the patient based on afirst triggering event. Further, the one or more processors may decreasea sympathetic tone to decrease the heart rate of the patient based on asecond triggering event. Further, the one or more processors maydecrease a parasympathetic tone to increase the heart rate of thepatient based on a third triggering event. Further, the one or moreprocessors may increase a parasympathetic tone to decrease the heartrate of the patient based on a fourth triggering event.

In another example, the one or more processors may increase thesympathetic tone to increase the heart rate of the patient based on asecond triggering event. Further, the one or more processors mayincrease the sympathetic tone to increase the heart rate of the patientbased on a third triggering event. Further, the one or more processorsincrease the sympathetic tone to increase the heart rate of the patientbased on an nth triggering event.

In another example, the one or more processors decrease a sympathetictone to decrease the heart rate of the patient based on a firsttriggering event. Further, the one or more processors decrease thesympathetic tone to decrease the heart rate of the patient based on asecond triggering event. Further, the one or more processors maydecrease the sympathetic tone to decrease the heart rate of the patientbased on a third triggering event. In addition, the one or moreprocessors decrease the sympathetic tone to decrease the heart rate ofthe patient based on an nth triggering event.

Cardio-protection in epilepsy is a rapidly growing field of vitalimportance. In this disclosure, systems, devices, and/or method ofprotecting the heart from standstill or fatal arhythmias are disclosed.Further in this disclosure, systems, devices, and/or methods ofautomated detections, warnings, reportings, treatments, controls and/orany combination thereof of ictal and peri-ictal chronotropic instabilityare shown.

In FIG. 17, a graph shows monotonic increase and decrease in heart rate.In FIG. 17, a first triggering event, a first warning event, and/or afirst therapy event 1702 are shown. Further, a second triggering event1704, a second warning event, and/or a second therapy event 1704 areshown. In addition, an Nth triggering event, an Nth warning event,and/or an Nth therapy event 1706 are shown. In FIG. 18, the heart rateof the patient increases which is followed by a decrease in heart rate,then an increase heart rate and a final decrease in heart rate. In thisexample, the first drop in heart rate crossed downwardly the detectionthreshold which would have temporarily disabled the warning system andthe delivery of the therapy. While the first peak was not temporallycorrelated with paroxysmal activity on any of the intra-cranialelectrodes used in this patient, it is likely that the first increase inheart rate was caused by epileptic discharges from a brain site that wasnot being investigated. In this example, the x-axis is time in hours andthe y-axis is heart beats per minute. In this example, an electrographiconset in the brain 1810 is shown and an electrographic termination inthe brain 1812 is shown.

In FIG. 19, a change in ictal heart rate is shown. In this example, thedrop in heart rate during the seizure, is even more prominent that theone depicted in FIGS. 17-18, as it is below the inter-ictal baseline. Itshould be noted that the oscillations in heart rate during thepost-ictal period are indicative of cardiac instability. In thisexample, a seizure onset point 1910 and a seizure termination point 1912are shown.

In FIG. 20, large amplitude tachycardia cycles occurringquasi-periodically after termination of paroxysmal activity recordedwith intra-cranial electrodes. While the mechanisms responsible forthese oscillations are unknown, the probability that they are epilepticin nature cannot be excluded, since electrographic and imaging data usedto guide intra-cranial electrode placement pointed to the existence ofonly one epileptogenic site.

In FIG. 21, small amplitude continuous quasi-periodic oscillationspreceding and following a seizure recorded with intra-cranial electrodes(same patient as FIG. 20). In various embodiments, ictal and peri-ictalcardiac instability are shown. The mechanisms leading to SUDEP have notbeen elucidated, in part due to the inability to record data during thecritical events that culminate in cardiac fibrillation or in standstill(or in respiratory arrest). In this example, a first triggering event, afirst warning event, and/or a first therapy event 2102 are shown.Further, an Nth triggering event, an Nth warning event, and/or an Nththerapy event 2104 are shown.

The data obtained in intractable epileptics undergoing epilepsy surgeryevaluation not only supports a cardiac mechanism (of course, not at theexclusion of catastrophic respiratory failure) but more specificallypoints to chronotropic instability as backdrop against which, lethalarrhythmias or cardiac standstill may ensue. Moreover, the instabilityis not restricted to the ictal period but, in certain cases, precedesand/or follows it for several minutes. FIGS. 17-21 illustrate thespectrum of instability in intractable epileptics. This phenomenon isreferred herein to as Ictal and Pre-Ictal Chronotropic Instability.

The challenges that for accurate quantification and delivery ofefficacious therapies, ictal chronotropic instability poses, wereaddressed and strategies to manage them are outlined. Here, theattention is focused on Ictal and Pre-Ictal Chronotropic Instability, amore prolonged and serious pathological phenomenon in intractableepileptics and on the vital issues of cardio-protection.

The aim of this disclosure is to contingently and adaptively dampenbased on the slope, amplitude, duration and “direction” (positive ornegative chronotropic and its magnitude relative to an adaptivebaseline/reference heart rate) the heart oscillations present before,during or after epileptic seizures.

While several embodiments may be envisioned, on embodiment (forefficacy, practicality and cost-effectiveness) is to electricallystimulate/activate the trunk or a branch of the right vagus nerve in thecase of elevations in heart (to reduce the heart rate, when there aremore than 2 consecutive oscillations/cycles or 1 that is large andprolonged. The intensity and duration of stimulation as well as otherparameters are determined by the slope, amplitude and duration of theoscillations, while ensuring adequate blood perfusion to all organs. Inthe case of negative chronotropic effects (decreases in heart rate) thetrunk or a branch of the right vagus nerve may be “blocked” usingcertain electrical stimulation techniques or through cooling; the effectof this intervention is to increase heart rate.

In one embodiment, the “height” of the oscillation is the only featureconsidered. While obviously important, this embodiment does not takeinto consideration a possibly more important feature: the rate at whichthe oscillation occurs: the consequences of waiting to intervene untilan oscillation reaches a certain height (e.g., 120 bpm) are different ifit takes, 30 seconds for the heart rate to reach the value than if ittakes 2 seconds to reach the value. Estimating the rate of change of theheart rate, provides life-saving information. Another aspect is theinter-maxima or inter-minima interval between oscillations. Having heartrate oscillation occur every 2-3 seconds is much more serious than every1-2 hours. In one example, one benefit may be that the window to act islengthen which can save lives. In one embodiment, a system for treatinga medical condition in a patient includes: a sensor for sensing at leastone body data stream; a heart rate unit which determines a heart rateand a heart rate oscillation of the patient based on the at least onebody data stream; and a logic unit which compares via one or moreprocessors a monitored value which is determined based on one or moredata points relating to the heart rate and to the heart rate oscillationto a threshold value, the logic unit determines a triggering event basedon the comparison where the one or more processors initiate one or moreactions to change the heart rate of the patient based on thedetermination of the triggering event.

In another example, the system includes at least one electrode coupledto a vagus nerve of the patient and a programmable electrical signalgenerator. Further, the one or more processors may increase asympathetic tone to increase the heart rate of the patient. In anotherexample, the one or more processors may decrease a parasympathetic toneto increase the heart rate of the patient. In another example, the oneor more processors may decrease a sympathetic tone to decrease the heartrate of the patient. Further, the one or more processors may increase aparasympathetic tone to decrease the heart rate of the patient. Inaddition, the system may include a seizure detection unit which analyzesthe at least one body data stream to determine an epileptic seizurestatus. The system may include at least one electrode coupled to a vagusnerve of the patient and a programmable electrical signal generatorwhere the one or more processors apply an electrical signal to the vagusnerve of the patient based on a determination that a seizure ischaracterized by a decrease in the heart rate of the patient and wherethe electrical signal is applied to block action potential conduction onthe vagus nerve. In addition, the heart unit may determine aninter-maxima interval and an inter-minima interval between a firstoscillation and a second oscillation. Further, the logic unit maycompare the inter-maxima interval and the inter-minima interval to aninterval threshold. In addition, the one or more processors may initiateone or more actions based on the interval threshold being reached.

The particular embodiments disclosed above are illustrative only as thedisclosure may be modified and practiced in different but equivalentmanners apparent to those skilled in the art having the benefit of theteachings herein. Furthermore, no limitations are intended to thedetails of construction or design herein shown other than as describedin the claims below. It is, therefore, evident that the particularembodiments disclosed above may be altered or modified and all suchvariations are considered within the scope and spirit of the disclosure.Accordingly, the protection sought herein is as set forth in the claimsbelow. In addition, all examples, embodiments, and/or elements may becombined in any manner that are disclosed in this document. In otherwords, an element from a first example (paragraph [0088]) can becombined with any other element, such as, a second element from an Nthexample (paragraph [0163]). For brevity, all these examples are notwritten out but are part of this document.

In another example, this disclosure relates generally to medical devicesystems and, more particularly, to medical device systems capable oftesting the responsiveness of a patient having brain state changes.Testing of responsiveness of a patient may be used to determine a timeat which loss of function for the patient occurs. Therapies usingelectrical currents or fields to provide a therapy to a patient(electrotherapy) are beneficial for certain neurological disorders, suchas epilepsy. Implantable medical devices have been effectively used todeliver therapeutic electrical stimulation to various portions of thehuman body (e.g., the vagus nerve) for treating various medicalconditions, including epilepsy. As used herein, “stimulation,”“neurostimulation,” “stimulation signal,” or “neurostimulation signal”refers to the application of an electrical, mechanical, magnetic,electro-magnetic, photonic, acoustic, physiological, cognitive, and/orchemical signal to a neural structure in the patient's body. The signalis an exogenous signal that is distinct from the endogenouselectro-chemical activity inherent to the patient's body and theenvironment. In other words, the stimulation signal (whether electrical,mechanical, magnetic, electro-magnetic, photonic, acoustic or chemicalin nature) applied to a cranial nerve or to other nervous tissuestructure in the present disclosure is a signal applied from a medicaldevice, e.g., a neurostimulator.

A “therapeutic signal” refers to a stimulation signal delivered to apatient's body with the intent of treating a medical condition through asuppressing (blocking) or modulating effect to neural tissue. The effectof a stimulation signal on neuronal activity may be inhibitory(suppressing) or excitatory (expressing); additionally, the effect maybe immediate (“all or none”) or the result of spatio-temporal summationof stimuli (modulation or biasing), a process that lacks the immediacyassociated with “all or none” responses. However, for simplicity, theterms “stimulation” and “modulation,” and variants thereof, are usedinterchangeably herein. In general, however, the delivery of anexogenous signal itself refers to “stimulation” of the neural structure,while the effects of that signal, if any, on the electrical activity ofthe neural structure are properly referred to as “modulation,” which maymanifest as either inhibition (suppression) or excitation (expression).Furthermore, depending upon myriad factors such as the history (recentand distant) of the nervous system, stimulation parameters and time ofday, to name a few, the effects of stimulation (with the sameparameters) upon the neural tissue may be excitatory or inhibitory,facilitatory or disfacilitatory and may suppress, enhance or leaveunaltered, the neuronal activity it intends to control. In spite ofthese vagaries, there is evidence of a suppressing effect of astimulation signal on abnormal neural tissue activity, specifically ofepileptic seizures (see Osorio et al., Ann Neurol 2005; Osorio & FreiIJNS 2009) Suppression of abnormal neural activity is a threshold orsuprathreshold process and the temporal scale over which it occurs isusually in the order of a few milliseconds to hundreds of milliseconds.Modulation of abnormal or undesirable neural activity, unlikesuppression is a “sub-threshold” process in the spatio-temporal domainthat may summate and result under certain conditions, in threshold orsuprathreshold neural events. The temporal scale of modulation is muchlonger than that associated with “all or none” responses. Waveannihilation or reduction through collision with identical, similar ordissimilar waves, or by “pushing” them (the waves) into their “nullspace” or “black hole” (Winfree; Osorio & Frei 2009) are techniques thatrely on stimulation but for which concepts of inhibition or excitationas conventionally used in electrophysiology may not apply. These formsof annihilation (via collision and phase resetting) fall within thepurview of wave mechanics and topology. Those skilled in the art realizethat there are multiple approaches (and mechanisms) for controllingundesirable oscillations via stimulation (see Osorio et al, Ann Neurol2005; Kalitzin et al.; Sunderam et al)

In some embodiments, electrotherapy may be provided by implanting anelectrical device, i.e., an implantable medical device (IMD), inside apatient's body stimulation of a nervous tissue, such as a cranial nerve.Generally, electrotherapy signals that perform neuromodulation aredelivered by the IMD via one or more leads or wirelessly. Whenapplicable, the leads generally terminate at their distal ends in one ormore electrodes, and the electrodes, in turn, are coupled to tissue inthe patient's body. For example, a number of electrodes may be attachedto various points of a nerve or other tissue inside a human body fordelivery of a neurostimulation signal.

While contingent (also referred to as “closed-loop,” “active,” or“feedback” stimulation (i.e., electrotherapy applied in response tosensed information, such as heart rate) stimulation schemes have beenproposed, conventional vagus nerve stimulation (VNS) is non-contingent,programmed periodic stimulation. Specifically, conventional vagus nervestimulation usually involves a series of grouped electrical pulsesdefined by an “on-time” (such as 30 sec) and an “off-time” (such as 5min). This type of stimulation is also referred to as “open-loop,”“passive,” or “non-feedback” stimulation. Each sequence of pulses duringan on-time may be referred to as a “pulse burst.” The burst is followedby the off-time period in which no signals are applied to the nerve.During the on-time, electrical pulses of a defined electrical current(e.g., 0.5-3.5 milliamps) and pulse width (e.g., 0.25-1.0 milliseconds)are delivered at a defined frequency (e.g., 20-30 Hz) for a certainduration (e.g., 10-60 seconds). The on-time and off-time parameterstogether define a duty cycle, which is the ratio of the on-time to thecombination of the on-time and off-time, and which describes thepercentage of time that the electrical signal is applied to the nerve.

In conventional VNS, the on-time and off-time may be programmed todefine an intermittent pattern in which a repeating series of electricalpulse bursts are generated and applied to a cranial nerve such as thevagus nerve. The off-time is provided to minimize adverse effects andconserve power. If the off-time is set at zero, the electrical signal inconventional VNS may provide continuous stimulation to the vagus nerve.Alternatively, the off time may be as long as one day or more, in whichcase the pulse bursts are provided only once per day or at even longerintervals. Typically, however, the ratio of “off-time” to “on-time” mayrange from about 0.5 to about 10.

In addition to the on-time and off-time, the other parameters definingthe electrical signal in conventional VNS may be programmed over a rangeof values. The pulse width for the pulses in a pulse burst ofconventional VNS may be set to a value not greater than about 1 msec,such as about 250-500 pec, and the number of pulses in a pulse burst istypically set by programming a frequency in a range of about 20-150 Hz(i.e., 20 pulses per second to 150 pulses per second). A non-uniformfrequency may also be used. Frequency may be altered during a pulseburst by either a frequency sweep from a low frequency to a highfrequency, or vice versa. Alternatively, the timing between adjacentindividual signals within a burst may be randomly changed such that twoadjacent signals may be generated at any frequency within a range offrequencies.

Of the approximately 60 million people worldwide affected with epilepsy,roughly 23 million people suffer from epilepsy resistant to multiplemedications (Kwan et al. 2000). In the USA alone, the annual cost ofepilepsy care is USD 12 billion (in 1995 dollars), most of which isattributable to subjects with pharmaco-resistant seizures (Begley et al.2000). Pharmaco-resistant seizures are associated with an increase inmortality and morbidity (compared to the general population and toepileptics whose seizures are controlled by medications) and withmarkedly degraded quality of life for patients. Seizures may impairmotor control, responsiveness to a wide class of stimuli, and othercognitive functions. The sudden onset of a patient's impairment of motorcontrol, responsiveness, and other cognitive functions precludes theperformance of necessary and even simple daily life tasks such asdriving a vehicle, cooking, or operating machinery, as well as morecomplex tasks such as acquiring knowledge and socializing.

The deleterious impacts of epilepsy on patients' health and well-beingare compounded by the inability to gather, among others, accurateinformation about event frequency and severity. Event diaries (generatedby the patient and/or caregivers) are utterly inadequate (Blum, 1996;Elger 2007) in that event counts/frequencies are grossly underestimatedand severity is not measurable due to: a) lack of useful, representativemetrics and b) the inability of even experts in the field(epileptologists) to precisely and objectively quantify them based onvisual observation. Automated means for quantification of eventfrequency and severity would allow the stratification of patients byseverity, estimation of risks injury and death, formulation ofprognosis, tracking the progression of the disorder, and objectiveassessment of therapeutic efficacy, without which advances are in thisfield are unlikely to occur or are meager. However, to our knowledge, nopractical automated means for quantification of event frequency andseverity using signals different from brain electrical signals arepublicly available as of this writing, let alone any suitable forrigorous and valid assessment of therapeutic efficacy.

In one aspect of the present disclosure, a method for determiningresponsiveness of a patient having brain state changes is provided. Themethod comprises receiving an indication of the occurrence of atriggering event; administering to the patient, in response to theindication, a test of responsiveness; and determining, based upon aresult of the test, at least one responsiveness parameter selected fromthe group consisting of (i) a time of occurrence of a change in thepatient's responsiveness, (ii) a duration of a change in the patient'sresponsiveness; (iii) a magnitude of a change in the patient'sresponsiveness, (iv) a time interval from the indication of eventoccurrence to a change in the patient's responsiveness, (v) a type ofchange in the patient's responsiveness, (vi) an estimation of a seizureseverity; (vii) a classification of a seizure into clinical orsubclinical; (viii) a classification of a clinical seizure into simplepartial, complex partial, or generalized; (ix) an assessment of efficacyof a therapy for the patient's medical condition; (x) an assessment ofthe state of the disease and formulation of a prognosis for the patient;(xi) an estimation of a risk of injury or death for the patient; and(xii) two or more thereof.

In another aspect of the present disclosure, a computer readable programstorage unit encoded with instructions that, when executed by acomputer, perform the method discussed above.

In another aspect of the present disclosure, a medical device system fordetermining a responsiveness of a patient having brain state changes,comprising a receiving unit adapted to receive an indication of atriggering event; a responsiveness testing unit adapted to administer atest of responsiveness to a patient in response to the indication; adetermination unit adapted to receive a result of the test ofresponsiveness from the responsiveness testing unit and to make at leastone determination selected from the group consisting of (i) a time ofoccurrence of a change in the patient's responsiveness, (ii) a durationof a change in the patient's responsiveness; (iii) a magnitude of achange in the patient's responsiveness, (iv) a time interval from theindication of event occurrence to a change in the patient'sresponsiveness, (v) a type of change in the patient's responsiveness,(vi) an estimation of a seizure severity; (vii) a classification of aseizure into clinical or subclinical; (viii) a classification of aclinical seizure into simple partial, complex partial, or generalized;(ix) an assessment of efficacy of a therapy for the patient's medicalcondition; (x) an assessment of the state of the disease and formulationof a prognosis for the patient; (xi) an estimation of a risk of injuryor death for the patient; and (xii) two or more thereof.

The impairment of motor function or of responsiveness that characterizescertain types of events, are associated with high risk for seriousinjuries, even death, and of inappropriate behavior that furtherisolates the patient socially. However, since in certain types of eventsthese impairments lag behind the onset of abnormal electrical brainactivity, a “natural” window exists during which intervention wouldminimize these risks. Automated warning of impending impairment of motorfunction or of responsiveness would minimize risk of injury and socialembarrassment, particularly in the case of certain complex partial andsecondarily generalized events, as well as allow patients to safelyperform certain activities precluded by this disorder.

Cranial nerve stimulation has been proposed to treat a number of medicalconditions pertaining to or mediated by one or more structures of thenervous system of the body, including epilepsy and other movementdisorders, depression, anxiety disorders and other neuropsychiatricdisorders, dementia, traumatic brain injury, coma, migraine headache,obesity, eating disorders, sleep disorders, cardiovascular disorders(such as congestive heart failure and atrial fibrillation),hypertension, endocrine disorders (such as diabetes and hypoglycemia),and pain (including neuropathic pain and fibromyalgia), among others.See, e.g., U.S. Pat. Nos. 4,867,164; 5,299,569; 5,269,303; 5,571,150;5,215,086; 5,188,104; 5,263,480; 6,587,719; 6,609,025; 5,335,657;6,622,041; 5,916,239; 5,707,400; 5,231,988; 5,330,515; 6,961,618;7,457,665; and 7,630,757; among others. Despite the numerous disordersfor which cranial nerve stimulation has been proposed or suggested as atreatment option, the mechanisms of action of stimulation for many (ifnot all) cranial nerves remain relatively poorly understood.

There is a wide range of medical disorders for which VNS may beprescribed. Among these, those manifesting with events characterized bysudden loss of consciousness (and inevitably of postural tone) or ofresponsiveness/awareness (without loss of consciousness and of posturaltone) are particularly hazardous and disabling to those who suffer fromthem. Loss of consciousness results invariably in falls to the groundwhich may be associated with serious bodily and brain injuries; loss ofresponsiveness (during which patients remain awake but lack discernment)are often the cause of serious vehicular and household accidents (suchas fires, burns). Sudden loss of consciousness may becardiovascular/autonomic or neurological in nature; loss of awareness isalmost always neurological in nature. Among the neurological causes ofloss of consciousness (with or without abnormal motor activity)epileptic seizures rank second to cardiovascular/autonomic dysfunction;for loss of responsiveness, epileptic seizures rank highest. Epilepticseizures are characterized by sudden, transient increases (above thenormal level) in neuronal membrane voltages, commonly associated withchanges in autonomic function. Seizures may affect all bodily functionsunder autonomic control, most notably cardio-respiratory and alsotemperature (Sunderam & Osorio), pupillary, skin resistance control,sphincter tone, peristalsis, etc. By identifying which bodily functionsare affected by an epileptic seizure, changes in the signals or indicesassociated with the affected function(s) may be used to detect seizuresautomatically. Specifically seizures may be detected via: a) brainelectrical signals recorded from the scalp (electroencephalogram; EEG)or directly from the brain (electrocorticogram; ECoG); b) autonomicsignals or indices such as changes in heart and respiratory activityrate, pupillary size. For example, increases in heart rates(tachychardia) and respiratory rates (tachypnea or hyperventilation)often occur in patients with partial seizures while they are motionless.The occurrence of autonomic changes during seizures is consistent withthe fact that autonomic functions are under the control of the brain(central nervous system) (Brodal) which is the site of epileptogenesisand ictiogenesis. Autonomic or neurologic index or indices is/are usedherein to refer to any detectable state or change of state reflective ofthe function of one or more aspects of the autonomic nervous system ofthe patient.

Although not so limited, a system capable of implementing embodiments ofthe present disclosure is described below. FIG. 22A depicts theimplantable medical system (IMD) 100 for implementing one or moreembodiments of the present disclosure. An electrical signal generator110 is provided, having a main body 112 comprising a case or shell witha header 116 for connecting to an insulated, electrically conductivelead assembly 122. The generator 110 is implanted in the patient's chestin a pocket or cavity formed by the implanting surgeon just below theskin (indicated by a dotted line 145), similar to the implantationprocedure for a cardiac pacemaker pulse generator.

A nerve electrode assembly 125, preferably comprising a plurality ofelectrodes having at least an electrode pair, is conductively connectedto the distal end of the lead assembly 122, which preferably comprises aplurality of lead wires (one wire for each electrode). Each electrode inthe electrode assembly 125 may operate independently or alternatively,may operate in conjunction with the other electrodes. In one embodiment,the electrode assembly 125 comprises at least a cathode and an anode. Inanother embodiment, the electrode assembly comprises one or moreunipolar electrodes.

Lead assembly 122 is attached at its proximal end to connectors on theheader 116 of generator 110. The electrode assembly 125 may besurgically coupled to the vagus nerve 127 in the patient's neck or atanother location, e.g., near the patient's diaphragm or at theesophagus/stomach junction. Other (or additional) cranial nerves such asthe trigeminal and/or glossopharyngeal nerves may also be used todeliver the electrical signal in particular alternative embodiments. Inone embodiment, the electrode assembly 125 comprises a bipolarstimulating electrode pair 126, 128 (i.e., a cathode and an anode).Suitable electrode assemblies are available from Cyberonics, Inc.,Houston, Tex., USA as the Model 302 electrode assembly. However, personsof skill in the art will appreciate that many electrode designs could beused in the present disclosure. In one embodiment, the two electrodesare wrapped about the vagus nerve, and the electrode assembly 125 may besecured to the vagus nerve 127 by a spiral anchoring tether 130 such asthat disclosed in U.S. Pat. No. 4,979,511 issued Dec. 25, 1990 to ReeseS. Terry, Jr. and assigned to the same assignee as the instantapplication. Lead assembly 122 may be secured, while retaining theability to flex with movement of the chest and neck, by a sutureconnection to nearby tissue (not shown).

In some embodiments, the electrode assembly 125 may comprise temperaturesensing elements and/or heart beat sensor elements for detection ofelectrical, mechanical or acoustic activity. Other sensors for otherautonomic indices may also be employed. Both closed-loop and open-loopstimulation may be combined or delivered by a single IMD according tothe present disclosure. Either or both modes may be appropriate to treata specific patient under observation.

The electrical pulse generator 110 may be programmed with an externaldevice (ED) such as computer 150 using programming software known in theart. A programming wand 155 may be coupled to the computer 150 as partof the ED to facilitate wireless radio frequency (RF) communicationbetween the computer 150 and the implanted pulse generator 110. Theprogramming wand 155 and computer 150 permit non-invasive communicationwith the generator 110 after the latter is implanted. In systems wherethe computer 150 uses one or more channels in the Medical ImplantCommunications Service (MICS) bandwidths, the programming wand 155 maybe omitted to permit more convenient communication directly between thecomputer 150 and the pulse generator 110.

Turning now to FIG. 22B, the depicted embodiment shows, in addition tothe IMD 100, a responsiveness testing input/output (I/O) unit 197 forimplementing one or more embodiments of the present disclosure. Theresponsiveness testing I/O unit 197 contains an input device 199, anoutput device 198, and a control and communication unit 196.

The output device 198 is configured to present an output to the patientwhen it receives instructions and/or commands to do so from the controland communication unit 196. By “output” is meant a visual, auditory,tactile, olfactory or gustatory stimulus or signal perceptible by one ormore of the senses of a patient. Exemplary output devices 198 include,but are not limited to, visual devices, such as LCD, LED, or otherdisplays, which may output a light, graphics, text, animation, or video,among others, or two or more thereof; audio devices, such as speakers,which may output sound, synthesized speech, recorded speech, or livespeech, among others, or two or more thereof; and tactile devices, whichmay output Braille text, vibration, heat, or cold, among others, or twoor more thereof. The output device 198 may also comprise two or more ofthe devices described above, among others; for example, the outputdevice 198 may comprise a visual device and an audio device, forexample, an LCD screen and a speaker, among others. In variousembodiments, the output device 198 may be housed in the medical device2300 or an external unit 2370.

The input device 199 is configured to receive an input from the patientwhen it receives instructions to do so from the control andcommunication unit 196. By “input” is meant any state or change in stateof the device effected by one or more actions of the patient. Exemplaryinput devices 199 include, but are not limited to, touchscreens,buttons, switches, microphones, and cameras, among others, or two ormore thereof. In various embodiments, the input device 199 may be housedin the medical device 2300 or an external unit 2370.

The control and communication unit 196, as mentioned, providesinstructions to the output device 198 to present an output and to theinput device 199 to receive an input. It also provides instructions forthe functions of a triggering event indication receiving unit (2365,FIG. 23B), a responsiveness testing unit (2385, FIG. 23B), aresponsiveness determination unit (2387, FIG. 23B), and a responsivenessparameter unit (2388, FIG. 23B), which functions each involve thereceipt of, transmission of, and internal handling of, data, as will bediscussed in more detail with reference to FIG. 23B, below.

The responsiveness testing I/O unit 197 is shown as a single discreteunit in FIG. 1B, but other embodiments are possible. The responsivenesstesting I/O unit 197 may be external to the patient's body, and in afurther embodiment, may be configured to be held in the hand. As shouldbe apparent, in other embodiments, the responsiveness testing I/O unit197 may not be configured to be held in the hand, but may instead beplaced elsewhere on the patient's body (e.g., on the wrist, among otherlocations), on a table, desk, nightstand, floor, or on, in, or otherwisesited with reference to a feature of the patient's environment. Thehardware, the software, or both of the responsiveness testing I/O unit197 may be especially designed for responsiveness testing, but need notbe; for example, in one embodiment, the responsiveness testing I/O unit197 is embodied as software in a cellular telephone, a smartphone (e.g.,an Apple iPhone® or a smartphone sold by BlackBerry, Palm, Motorola,HTC, or the like), a personal digital assistant (PDA), or anotherprogrammable handheld electronic device (e.g., an Apple iPod®). Inanother embodiment, the responsiveness testing I/O unit 197 is embodiedas software on a netbook, notebook, or desktop computer, such as onerunning an operating system such as Microsoft Windows, Apple MacintoshOS X, or Linux, among others. In some embodiments, the patient may beprovided with a plurality of responsiveness testing I/O units 197,networked together in a system capable of receiving inputs and providingoutputs to any of the units 197 comprising the network. For certainapplications the responsiveness testing I/O unit 197 may be implantedinto the patient's body.

Also, in various embodiments, portions of the responsiveness testing I/Ounit 197 may be housed in separate units. For example, the output device198 may be a monitor or a speaker of a computer, and the input device199 may be a touchscreen, button, switch, microphone, or camera embodiedin a handheld device. For another example, the output device 198 may bea monitor or a speaker of a handheld device, and the input device 199may be a keyboard, mouse, microphone, or camera of a computer. For stillanother example, the output device 198 may be a monitor or a speaker ofa handheld device, and the input device 199 may be a magnetic swipesensor or a tap sensor of the IMD 100.

Also, although FIG. 22B shows the responsiveness testing I/O unit 197 inproximity to the IMD 100, as should be apparent, the responsivenesstesting I/O unit 197 may be used entirely separately from the IMD 100.For example, a patient having brain state changes may use theresponsiveness testing I/O unit 197 without having the IMD 100 implantedwithin his or her body. In such embodiments, the disclosure may lack anyimplanted component. Thus, IMD 100 may be absent and the disclosure maycomprise responsiveness testing I/O unit 197 alone or with an externalmedical device.

Turning now to FIG. 23A, a block diagram depiction of the medical device(MD) 2300 is provided, in accordance with one illustrative embodiment ofthe present disclosure. The MD 2300 (such as implantable generator 110from FIG. 22A) may comprise a controller 2310 capable of controllingvarious aspects of the operation of the MD 2300. In some embodiments,the controller 2310 is capable of receiving data and causing a therapyunit 2320 to generate and deliver a therapy, such as an electricalsignal to target tissues of the patient's body for treating a medicalcondition using, for example, electrodes 2326, 2328. Therapy unit 2320is optional, as indicated by the dotted line. In some embodiments,therapy unit 2320 is absent. For example, the controller 2310 mayreceive instructions from another device, or may cause the electricalsignal to be generated and delivered based on calculations andprogramming internal to MD 2300. The controller 2310 is capable ofaffecting substantially all functions of the MD 2300. The MD 2300 may bean external device, or in an alternative embodiment, an implantablemedical device.

The controller 2310 may comprise various components, such as a processor2315, a memory 2317, etc. The processor 2315 may comprise one or moremicrocontrollers, microprocessors, etc., capable of performing variousexecutions of software components. The memory 2317 may comprise variousmemory portions where a number of types of data (e.g., internal data,external data instructions, software codes, status data, diagnosticdata, etc.) may be stored. The memory 2317 may comprise one or more ofrandom access memory (RAM), dynamic random access memory (DRAM),electrically erasable programmable read-only memory (EEPROM), flashmemory, volatile memory, non-volatile memory, etc.

In one embodiment, MD 2300 may be an implantable medical device, andcoupling 2301 may comprise a lead assembly such as lead assembly 122(FIG. 22A). In another embodiment, MD 2300 may be external to thepatient's body, and may be coupled to an implanted lead via a wirelessor inductive coupling, such as an RF inductive coupling. In a stillfurther embodiment, MD 2300 may be external to the patient's body andelectrodes 2326, 2328 may also be external to the patient's body.Whether MD 2300 is an implantable or external unit, a therapeuticelectrical signal may be delivered to the electrodes 2326, 2328 by thetherapy unit 2320 based upon instructions from the controller 2310. Thetherapy unit 2320 may comprise various circuitry, such as electricalsignal generators, impedance control circuitry to control the impedance“seen” by the leads, and other circuitry that receives instructionsrelating to the delivery of the electrical signal to tissue. Therapyunit 2320 may be configured to deliver biphasic, charge balanced pulses,multiphasic pulses, or monophasic pulses. Therapy unit 2320 may deliverconstant current or constant voltage. Further, therapy unit 2320 may beconfigured to deliver magnetic currents, or to operate as a drugadministration and/or thermal control unit.

In other embodiments, coupling 2301 is operatively coupled to anelectrode, wherein the electrode is adapted to be coupled to at leastone of a portion of a brain structure of the patient, a cranial nerve ofa patient, an organ for special senses of a patient, the spinal cord ofa patient, a spinal cord root of a patient, a sympathetic nervestructure of the patient, a peripheral nerve of the patient, the skin ofthe patient, or a muscle of the patient.

In some embodiments, therapy unit 2320 as well as coupling 2301 andelectrodes 2326, 2328 may be omitted. In other words, the responsivenesstesting described herein can be performed by MD 2300 whether or not atherapy for the patient's medical is provided.

The MD 2300 may also comprise a power supply 2330. The power supply 2330may comprise a battery, voltage regulators, capacitors, etc., to providepower for the operation of the MD 2300, including delivering thetherapeutic electrical signal. The power supply 2330 comprises a powersource that in some embodiments may be rechargeable. In otherembodiments, a non-rechargeable power source may be used. The powersupply 2330 provides power for the operation of the MD 2300, includingelectronic operations and the electrical signal generation and deliveryfunctions. The power supply 2330 may comprise a lithium/thionyl chloridecell or a lithium/carbon monofluoride (LiCFx) cell for implantableembodiments, and more common watch batteries or 9 volt batteries fornon-implantable embodiments. Other battery types known in the art ofimplantable medical devices may also be used. Where MD 2300 is externalto the patient's body, for example, power supply 2380 may comprise aphoto-voltaic or solar cell.

The MD 2300 may also comprise a communication unit 2360 capable offacilitating communications between the MD 2300 and various devices. Inparticular, the communication unit 2360 is capable of providingtransmission and reception of electronic signals to and from an externalunit 2370, such as computer 150 and a wand 155 that can communicate withthe MD 2300 remotely (FIG. 22A). The communication unit 2360 may includehardware, software, firmware, or any combination thereof.

It should be noted that any of the connections 2301, 2311, 2377, 2397,or that between external unit 2370 and database unit 2350 may be wiredor wireless, as a matter of routine skill for the person of ordinaryskill in the art having the benefit of the present disclosure.

Also, the MD 2300 may comprise a cost of testing unit 2361 capable ofdetermining at least some of the costs associated with responsivenesstesting of the patient. For example, the cost of testing unit 2361 maycalculate power consumption by the various units associated with testingthat are described herein, consumption of computational resources by thevarious units associated with testing, or the like. This information maybe useful to the clinician in order to allow him or her to adjust thenumber, difficulty, or other parameters of the responsiveness testsadministered to the patient.

The MD 2300 may also comprise one or more sensor(s) 2312 coupled viasensor coupling 2311 (which may comprise a lead or an inductivecoupling) to the MD 2300. The sensor(s) 2312 are capable of receivingsignals related to a body parameter, such as an autonomic or neurologicindex, and delivering the signals to the MD 2300. In a particularembodiment, the sensor(s) 2312 deliver the signals to the controller2310, where they may be processed by the processor 2315 and/or stored inthe memory 2317, and/or routed to the triggering event indicationreceiving unit 2365, as discussed below.

Exemplary sensor(s) 2312 include electrocardiography (EKG) devices,accelerometers, inclinometers, pupillometers, face or body temperaturemonitors, skin resistance monitors, and/or sound and pressure sensors,among others.

In one embodiment, the sensor(s) 2312 may be the same as stimulatingelectrode(s) 2326, 2328. In other embodiments, the sensor(s) 2312 areseparate structures that may be placed in, on, or near a particularorgan, tissue, nerve, or blood vessel of the patient, or outside thepatient's body, such as on the patient's skin or in the patient'senvironment.

In one embodiment, the MD 2300 may comprise a triggering eventindication receiving unit 2365 that is capable of receiving signalsrelated to a triggering event. The triggering event indication receivingunit 2365 may be capable of performing any necessary or suitableamplifying, filtering, and performing analog-to-digital (A/D)conversions on the received signals to determine whether a triggeringevent has occurred. The triggering event indication receiving unit 2365,in one embodiment, may comprise software module(s) that are capable ofperforming various interface functions, filtering functions, etc., todetermine whether a triggering event has occurred. In another embodimentthe triggering event indication receiving unit 2365 may comprisehardware circuitry that is capable of performing these functions. In yetanother embodiment, the triggering event indication receiving unit 2365may comprise hardware, firmware, software and/or any combinationthereof.

The triggering event indication receiving unit 2365 may determinewhether a triggering event occurred, wherein the triggering event isselected from the group consisting of a) an indication from a medicalevent detection algorithm that a medical event is occurring or isimminent; b) a manual signal to administer the responsiveness test tothe patient; or c) a command to administer a responsiveness test to thepatient in the absence of an indication from a medical event detectionalgorithm that a medical event is occurring or imminent.

The triggering event for testing responsiveness may include one or moreof a) an indication from a medical event detection algorithm, based uponone or more body parameters of the patient, that a medical eventrelevant to the patient's condition is occurring or is imminent (e.g.,detection of a future, imminent, or on-going epileptic seizure or othermedical event using heart or other autonomic indices or brain activityof the patient, which may also be described as a positive or affirmativeoutput of a medical event detection algorithm (POMEDA)), b) a manualsignal from a patient, caregiver or physician to administer theresponsiveness test to the patient, or c) a command to administer aresponsiveness test to the patient in the absence of an indication froma medical event detection algorithm that a medical event is occurring orimminent (e.g., a command to administer a responsiveness test to thepatient during a negative output of a medical event detection algorithm(NOMEDA)). The command provided in the absence of a medical eventdetection event may be based upon circadian or ultradian rhythms of thepatient, past medical event history of the patient (e.g. times of day,week, or month when medical event probability exceeded a specifiedvalue), expiration of a random or pseudorandom timer or similar events.Elapse of a periodic, random, or pseudorandom time period may be used topresent a responsiveness test to the patient in response to a NOMEDA soas to: a) establish a representative baseline (e.g., non-seizure)performance for comparison (statistical) with that associated withmedical events, including a post-medical events period during whichperformance or responsiveness may remain impaired for some time; b)avoid anxiety or conditioning of the patient to expect a medical eventswhenever a test is administered, and c) to minimize biasing testresponses.

The end of a time period may be determined either by comparing thecurrent absolute time with a time previously determined to indicate theend of the time period, or by incrementing a counter of time units untila value previously determined to indicate the end of the time period isreached. For example, the time period may be programmed to have apredefined or random duration with a specified range, e.g., from 15minutes to 24 hours, or may be programmed as a specific number of randomtimepoints within a 24 hour period or weekly period. Tests in responseto a NOMEDA can be administered while the patient is awake to establisha representative baseline performance, since response times and othermeasures of cognitive performance vary as a function of circadianrhythms. For statistical purposes, it may also be desirable toadminister tests at about the same time of day on consecutive days;and/or at about the same time of a day as a medical event that occurredon a previous day; among other possibilities. To ensure statisticalvalidity, in one embodiment the logic associated with administering thetest in response to what is believed to be a NOMEDA may verify that theoutput of any medical event detection algorithm is, in fact, negative(i.e., that no medical event is occurring or imminent, as contrastedwith the simple expiration of a timer) before the test is applied andlogged as having occurred in response to a NOMEDA.

The previously determined time (for testing purposes) may be set at anypoint prior to the end of the time period, and may be programmed orreprogrammed by the manufacturer or the practitioner. For example, theratio of “non-algorithm-triggered” (i.e., manual or NOMEDA) to“algorithm-triggered” (i.e., POMEDA) events can be programmed, e.g.,about equal POMEDA and NOMEDA testing, 50% more (or less) NOMEDA testingthan POMEDA, or increased testing (both POMEDA and NOMEDA triggered) asa function of when (e.g., time of day, time of week, etc.) the patienthistorically has an increased probability of medically relevant events.

For POMEDA-triggered testing, a change in an autonomic or neurologicindex may be determined by receiving a value related to an autonomic orneurologic index and comparing it with a previously determined value.The autonomic or neurologic index value may be determined by analyzingat least one set of signals received from the patient and selected fromthe group consisting of cardiovascular signals, breathing signals,pupillary signals, skin signals, blood pressure, among others.Additionally or alternatively, neurological signals, such as thosegenerated by the brain or cranial nerves or body kinetic signals (e.g.,signals generated by motion of the patient's body as determined by anaccelerometer or inclinometer) may be used for detecting medicallyrelevant events, such as epileptic seizures.

For example, the autonomic or neurologic index value(s) used todetermine whether a medical event has occurred may be the heart rate, achange in the heart rate, or the rate of change in heart rate, and thetriggering event may be a heart rate above a first previously determinedvalue, a heart rate below a second previously determined value, or arate of change of heart rate above a third previously determined value,a heart rate variability above or below a fourth or fifth previouslydetermined value, among others. Other cardiovascular indices valuesinclude, but are not limited to, blood pressure, heart sounds, heartrhythm, heartbeat wave morphology, heartbeat complex morphology, or theshape of the deflection of the thoracic wall as the heart apex beatsagainst it, among others. Such cardiovascular index values can bedetected by electrocardiography, blood pressure monitors, a microphone,or apexcardiography, among others.

For another example, the autonomic or neurologic index value(s) used todetermine whether a medical event has occurred may be related to therespiration (breath) rate, and the triggering event may be a respirationrate above a first previously determined value, a respiration rate belowa second previously determined value, or a rate of change of respirationrate above a third previously determined value, among others. Otherrespiratory index values include, but are not limited to, respirationpattern, airflow velocity, respiration amplitude (tidal volume), oxygensaturation, arterial gas concentrations, and blood pH, among others.Such respiratory index values can be detected by techniques andapparatus known to the person of ordinary skill in the art.

For still another example, the autonomic or neurologic index value(s)used to determine whether a medical event has occurred may be related toone or more skin signals, such as a change in the skin resistivity ofthe patient.

For another example, the autonomic or neurologic index value(s) used todetermine whether a medical event has occurred may be related to one ormore temperature signals, such as a change in the skin temperature of apart of the patient's face (e.g., face) (see Sunderam & Osorio) or achange in the core temperature of the patient.

For still another example, brain signals, such as those determinable byan EEG or ECoG may be used to determine whether a medical event hasoccurred, and the triggering criterion may be a value of one or more ofthe brain signals above a first previously determined value or below asecond previously determined value.

For another example, the detection criterion may be related to one ormore body kinetic signals. The body kinetic signal may be determinableby electromyography, an accelerometer, and/or an inclinometer, and thetriggering criterion may be a value of the body kinetic signalindicative of the body's (or of a portion thereof such as an arm or aleg) acceleration, direction, position, amplitude or force of movements.

For yet another example, the index value(s) used to determine whether amedical event has occurred may be related to one or more cranial nervesignals.

For yet another example, the index value(s) used to determine whether amedical event has occurred may be related to one or more autonomic nerveor ganglia signals.

For still a further example, a plurality of autonomic and/or neurologic(e.g., brain, cranial nerve, or kinetic) index value(s) may be used todetermine whether a medical event has occurred. For example, thetriggering event may be a finding that the patient's heart rate is abovea threshold value at a time when a body kinetic signal shows thepatient's body orientation is reclined or when it indicates the patientstopped moving.

For POMEDA-triggered testing, the algorithm used may be one thatdetermines a probability of a medical event and yields a positive outputif the probability of the medical event exceeds a threshold. Forexample, one or more autonomic or neurologic indices may be assigned aweight, such as in the range 0 to 1, based on its history of sensitivityand/or specificity regarding the patient's medical condition; the timeof day, time of week, time or month, time of year, the patient'swake/sleep status, the patient's physical activity level, the patient'scurrent or recent food intake; or the like. The index value(s) may beanalyzed to produce an output value, e.g., a probability, p. If theprobability exceeds a threshold, a positive output may be yielded by thealgorithm.

Whether a seizure occurred may be determined by analyzing a change in anautonomic or neurologic index value, temporal or other patterns, ormorphologies, such as those discussed above; by receiving an input froma medical event detection algorithm; or by receiving an input from aclinician or knowledgeable layperson who observes anelectroencephalographic or clinical onset of a seizure. Such analysis isknown, for example, from work by the present inventors, such as U.S.Pat. Nos. 7,457,665; 6,961,618; and 6,549,804, hereby incorporated byreference herein.

The triggering event indication receiving unit 2365 is capable ofreceiving an indication of a triggering event and communicating suchreceipt to the controller 2310. Based upon the indication received bythe triggering event indication receiving unit 2365, a responsivenesstesting unit 2385 may administer a test of responsiveness to thepatient.

“Responsiveness” is used herein to refer to any response made by apatient upon exposure to a stimulus.

“Motor function” is used herein to refer to a function actuated by thecontraction of at least one muscle of the patient.

In one embodiment, responsiveness is part of a cognitive function.“Cognitive function” is used herein to refer to an action that indicatesto an observing adult of at least average intelligence and mental healththat the patient is purposefully implementing a behavior in pursuit ofan objective. Examples of cognitive functions include, but are notlimited to, attention, short-term memory, long-term memory, languagefluency, visuospatial awareness, abstract reasoning, or two or morethereof.

In another embodiment, the test of responsiveness can test the patient'sreflex function.

In a system as complex as the human body, the person of ordinary skillin the art would understand that for a cognitive function to be observedand/or measured, the cognitive function implements a motor function.

In certain embodiments, a positive test of motor function may revealpurposive behavior was performed by the patient to yield that positivetest, i.e., a positive test of motor function in these embodiments maybe further taken as a positive test of cognitive function. The converseis not necessarily true. In other words, a negative test of cognitivefunction may be coincident with various motor functions, such asnon-purposive movement of limbs, non-purposive vocalization, etc. Forexample, a patient with cognitive impairment may experience certainreflex motions or “automatisms” that are not to be confused as positiveevidence of cognitive function.

In certain embodiments, a test of responsiveness may distinguish betweenalertness (ability to orient to new stimuli) and attentiveness (abilityto engage and decode stimuli).

A “test of responsiveness” is any combination of one or more outputs tothe patient (such as one or more outputs provided by output device 198)and one or more responsiveness inputs received from the patient (such asone or more inputs provided by input device 199 or patient input unit2375). Typically, it will take some length of time for the human brainto decode a stimulus and encode a response, whether correct orincorrect.

In the embodiment shown in FIG. 23A, the function of the input device199 (FIG. 22B) is performed by patient input unit 2375. The patientinput unit 2375 may include a magnetic signal input sensor (such as, forexample, a Reed switch) or a tap input sensor, among others. In oneembodiment, the patient input unit 2375 may also be used to allow thepatient to request of the medical device 2300 alterations in a therapyregimen, such as to relieve an acute symptom of the patient's disease,to intervene with the intent of forestalling a medical event, or tominimize adverse effects of the therapy at particular times.

Results of the test of responsiveness include, but are not limited to,the correctness of an input and the time required by the patient toprovide the input after receiving the output. From the various resultsof the test, one or more measures of the patient's responsiveness may becalculated, as will be discussed in more detail below.

In certain embodiments, one or more autonomic and/or neurologic indicesmay give information relating to the patient's attention and/or effortgiven to the test. For example, pupillary information, such as blinkfrequency, blink duration, fixation frequency, dwell time, saccadicextent, and mean pupil diameter, any or all of which may be normalizedfor ambient lighting or other environmental factors, and/or to abaseline, can be used by the person of ordinary skill in the art todetermine whether the patient is paying attention to the test. Foranother example, electromyography (EMG) may give information about thepatient's facial muscle tone, which can be used by the person ofordinary skill in the art to gauge the patient's effort given to thetest.

In one embodiment, the test comprises the serial and simultaneouspresentation of a pair of visual “stimuli” (such as the letter “A” and asquare “□”) on a output device 198 (FIG. 1B). The position of the letteron either half of the screen (i.e., left “A □”, or right “□ A”) may berandomly chosen for each presentation and the patient instructed toimmediately make an input according to which side of the screen (left orright) on which the letter A appears. In one embodiment, the inputcomprises pressing one of two buttons, one button representing left andthe other representing right. A correct press may then correspond topressing the button ipsilateral to the side of the screen where theletter A was displayed. Test complexity may be increased (as needed) bydisplaying the stimuli in the vertical plane and alternating this(randomly) with the horizontal display or by randomly switching betweenstimuli during a test. For example, the patient may be instructed topress the button ipsilateral to the letter, except when the square isfilled with a solid color (other than the background color), in whichcase the button ipsilateral to the side where the filled square appearsshould be pressed. This test may be triggered by a POMEDA or in responseto a NOMEDA to allow comparison and quantification of changes inperformance during algorithm-triggered and non-algorithm-triggeredperiods.

During the test, as soon as the subject presses either button, or aftera maximal presentation time (e.g., 1 s) had elapsed, in case of noresponse, each stimulus presentation is removed (resulting in a blankscreen) until the next stimuli. At the end of each presentation, arandom timer (with appropriate upper and lower limits) can be set, theexpiration of which triggers the next presentation. A fixed number ofstimuli, such as 36, may be presented in each testing session, or thenumber of stimuli may be made a function of event duration and/orseverity as derived from an autonomic or neurologic index value, or thenumber of stimuli may be made a function of results of one or moreprevious stimuli (e.g., if the patient's results show substantially fullcognitive function for one or more trials of an seizure test, the numberof further stimuli may be increases to better assess cognitiveperformance). Inter-trial presentation time intervals may, in oneembodiment, be randomly chosen from a finite set of time intervals, suchas from the set {0.5 s, 1.0 s, 1.5 s, 2.0 s}, to minimize adaptation andbetter assess performance.

Although a single test may be administered to the patient, such asduring a medical event, such as a seizure, in other embodiments,multiple identical or different tests may be administered. In oneembodiment, when the patient's medical condition is epilepsy, tests canbe administered at a plurality of times, wherein at least one of theplurality of times is ictal (i.e., during an epileptic medical event)and at least one of the plurality of times is nonictal (i.e., at a timenot during an epileptic medical event). A test administered at anonictal time may be referred to herein as a “baseline” test. Inembodiments wherein the patient's medical condition is not epilepsy,tests may similarly be administered during a medical event, not during amedical event, and/or during other times.

The baseline test or the difficulty thereof may be adjusted by theclinician in view of the patient's general condition, e.g., a pediatricpatient, a geriatric patient, or a mentally challenged patient mayrequire a simpler baseline test, if the patient has difficultycompleting a more complicated baseline test in a short period of time.

The test may also be administered to patients suffering fromneurological or psychiatric disorders and/or to subjects free from suchdisorders.

The patient's responsiveness may be determined by responsivenessdetermination unit 2387. The responsiveness may be determined from oneor more values extractable from results of the test, such as thecorrectness of an input (such as a fraction or percentage of correctinputs), or the time required by the patient to provide the input afterreceiving the output, among others.

In one embodiment, multiple separate tests may be administered havingvarious difficulty levels or the level of difficulty of a single testmay be increased gradually or suddenly or different levels of difficultymay alternate randomly. For example, in one embodiment, a first test ofresponsiveness having a first difficulty level is selected andadministered, and, based on the results of the first test, a second testof responsiveness having a second difficulty level is selected andadministered. For comparison purposes, these tests could be administeredto patients during POMEDA periods and NOMEDA periods (e.g., for epilepsypatients, during seizure and non-seizure conditions), and comparisonscould be performed between tests of equivalent difficulty.

In one embodiment, the difficulty and duration of the degree ofresponsiveness test may be optimized according to the cost of detectionor the clinician's desired balance of sensitivity (low false negativerate) and specificity (low false positive rate), and/or to account forchanges in event severity over time. Doing so may require co-analysis ofthe degree of responsiveness test results with another indicator of amedical event, such as can be read from an autonomic (e.g., heart rate)or neurologic, (e.g., EEG) of the patient, or some other indicator thatmay exist or be developed.

In one embodiment specific to epilepsy patients, at the termination of adegree of responsiveness test, whether triggered by a POMEDA or not, thepatient may be asked if he or she just had a seizure. This is a way toclassify seizures as clinical or subclinical and an indirect way tovalidate detections; the patient's time-stamped response will be routedto the local database unit 2355 and/or the memory 2317, where it will becross-referenced with an autonomic or neurologic index value if oneindicative of a seizure exists at about the time the patient's responsewas recorded. If the patient indicates a seizure has occurred and anindex indicative of a seizure exists about the time of the response(i.e., the test was triggered by a POMEDA) it is classified as clinical.If the patient responds in the negative and the index value isindicative of a seizure, it is classified as subclinical. If the patientresponds that a seizure has occurred and none of the indices supports it(i.e., the test was triggered by a NOMEDA), a false negative detectionis recorded. This provides quantitative information about the status ofthe patient's condition and about therapeutic and/or diagnostic efficacythat is not currently available and complements that provided by seizurefrequency measures. It may also allow qualitative validation of otherseizure severity measures. Additionally, interrogating the patient aftera test has been administered, may help blind the patient to whether thetest was triggered by a POMEDA, and thus whether a seizure is occurringor imminent. Asking the patient if a seizure occurred afteradministration of a test may be programmed to take place after each testuntil a sample sufficiently large to support statistical analyses hasbeen collected, and updated based on the status of the patient'scondition and the response to therapy and/or diagnosis.

In one embodiment, the responsiveness determination unit 2387 canperform a quantification of one or more measures relating to the testresults and/or the patient's responsiveness. For example, if the test ofresponsiveness encompasses tracking the response time of the patient todeliver a correct answer to a stimulus (viz., speed of response), theresponse time of a plurality of trials can be tracked and quantified,such as by use of measures of central tendency. The percent of correctresponses may be also quantified and used alone or in conjunction withthe speed of response to mark the time of onset of lack ofresponsiveness, and its duration.

More specifically, based on the patient's responsiveness, theresponsiveness parameter unit 2388 may determine a time of occurrence ofa change in the patient's responsiveness, a duration of a change in thepatient's responsiveness; a magnitude of a change in the patient'sresponsiveness, a time interval from the indication of triggering eventoccurrence to a change in the patient's responsiveness; a type (e.g.,motor, cognitive, or both) of change in the patient's responsiveness, adetermination of medical event severity for the patient; a formulationof a prognosis for the patient; an estimation of a risk of injury ordeath for the patient; and an assessment of efficacy of a therapy forthe patient's medical condition, or some other parameter. Thedetermination may require acquisition of an adequate sample or samplesof patient results of responsiveness tests. For example, theresponsiveness parameter unit 2388 may compare the patient'sresponsiveness at a first time to a database of time-ordered priormeasures of responsiveness (which may be patient-specific or data from aplurality of patients), which may be stored in local database unit 2355or database unit 2350, and then review the set of measures in thedatabase taken from time points after each appearance in the database ofa measure reflective of the patient's responsiveness at the first timeto determine whether the patient is having a medical event, thepatient's baseline responsiveness, the patient's long-term prognosis, orthe like.

Strictly speaking, in embodiments where the medical condition isepilepsy, the seizure severity calculated here relates to loss offunction, not a seizure as an electroencephalographic event. However,the duration, severity, or both of a loss of function may be used asreasonable approximations and/or indicators of the duration and severityof at least some types of seizure.

For example, if a plurality of trials of a responsiveness test aretriggered by a POMEDA, the medical event duration may be approximated asthe time between the first iteration of the test in which the patientresponded incorrectly or failed to respond to three consecutivelypresented stimuli and the next subsequent iteration of the test in whichthe patient responded correctly. Another relevant measure ofseverity—the latency from seizure detection to loss of function—may bedetermined by the time between an indication of event occurrence (e.g.,a POMEDA) to the first iteration of the test in which the patientresponded incorrectly. Changes in the latency from seizure detection toloss of function over time may be used to determine whether thepatient's disease state is improving, worsening, or remains about thesame.

For example, if the speed of response, the correctness of the response,and/or the difficulty of response are logged for each of a plurality ofiterations of the test, the sum of response times for iterations abovethe baseline (optionally weighted by the correctness and/or difficulty)and the times at which those iterations were administered can be used tocalculate an area under the curve, from which a medical event severitycan be, in full or in part, approximated.

In various embodiments, one or more of the units or modules describedabove may be located in an external unit 2370 or a remote device 2392,with communications between that unit or module and communication unit2360 in the MD 2300 taking place via a link 2377, which may comprise alead, an inductive RF or similar wireless coupling, a Bluetooth or otherwireless data transfer coupling, etc. For example, in one embodiment, asshown in FIG. 23B, a triggering event indication receiving unit 2365, aresponsiveness testing unit 2385, a responsiveness determination unit2387, and a responsiveness parameter unit 2388 may be located in anexternal unit. In embodiments in which no therapy unit 2320 orstimulation electrodes 2326, 2328 are provided, all of the functionalmodules may be provided in an external unit.

In one embodiment, the external unit 2370 may comprise a local databaseunit 2355. Optionally or alternatively, the external unit 2370 may alsobe coupled to a database unit 2350, which may be separate from externalunit 2370 (e.g., a centralized database wirelessly linked to externalunit 2370). The database unit 2350 and/or the local database unit 2355are capable of storing various patient data. In certain embodiments, thememory 2317 is also capable of storing various patient data. These datamay comprise time stamped: a) patient responsiveness data, includingtest results and measures of responsiveness, b) number of detections(i.e., POMEDAs) and their severity expressed numerically as the productof peak index value and the time (in sec or min) which the index valuespends above a baseline; c) medical event classification (e.g., whethera seizure is clinical or subclinical, and if clinical, if it is simplepartial, complex partial, or generalized); d) therapy parameter data; e)disease status as assessed with autonomic and neurological indices; f)injury risk; h) event button presses or patient input, all data beingupdated as its flow rate demands (as will be discussed in more detailbelow). The time stamp may have any particular desired granularity, suchas to the hundredth of a second. The database unit 2350 and/or the localdatabase unit 2355 may comprise data for a plurality of patients, andmay be organized and stored in a variety of manners, such as in dateformat, severity of disease format, latency (time difference) between adetection event (i.e., a POMEDA) and a loss of responsiveness asindicated by the failure of the patient to respond to one or more teststimuli, etc. The database unit 2350 and/or the local database unit 2355may be relational databases in one embodiment. The database unit 2350and/or the local database unit 2355 may store various patient data.

In one embodiment, the database unit 2350 and/or the local database unit2355 allow the patient, a caregiver, a medical practitioner, or anotherinterested person to follow the patient's responsiveness under variouschanging conditions, such as under various disease conditions (e.g., forepilepsy patients, during preictal, ictal, and/or postictal times),various times of day, month, and/or year, various therapy parameters,etc.

FIGS. 24A-24B contain many like elements to FIGS. 23A-23B, and thoselike elements will not be described further. FIGS. 24A-24B contain amedical event characterization unit 2489, comprising a medical eventquantification unit 2490 and a medical event classification unit 2491.Based on either or both of the patient's responsiveness and one or moreother indicators of a medical event (e.g., a POMEDA from an algorithmbased on the patient's heart rate or heart rate variability, amongothers), the medical event quantification unit 2490 may determine aduration or a severity of a medical event and/or the medical eventclassification unit 2491 may classify the medical event by duration,severity, and/or estimated type (e.g., for seizures, partial orgeneralized, simple or complex, etc.). For example, the medical eventcharacterization unit 2489 may determine a series of measures in adatabase of time-ordered values, which may be stored in local databaseunit 2355 or database unit 2350, in which many or all of the measuresreflected a medical event, and determine the duration of a medical eventby comparing time-stamps of the first and last values in the seriescomparable to a measure of the patient's baseline responses. A severityof a medical event may, for example, be calculated from the sum,average, median, mean, nth percentile, or area under the curve of one ormore measured values in the series.

FIGS. 25A-25B contain many like elements to FIGS. 23A-23B or FIGS.24A-24B, and those like elements will not be described further. FIGS.25A-25B illustrate an embodiment of the disclosure having a therapyevaluation unit 2590. Therapeutic efficacy of a therapy provided by atherapy unit 2320 can be assessed by determining if there is a decreasein the severity or duration of the patient's loss of responsiveness overtime. Decreases in value of any of the autonomic or neurologicindices—including electrical activity recorded directly from thebrain—do not provide direct or reliable information about the state of apatient's responsiveness. Based on the patient's responsiveness, thetherapy evaluation unit 2590 may determine an efficacy of a therapy fora patient's medical condition. For example, the therapy evaluation unit2590 may compare a measure of the patient's responsiveness when atherapy is administered by a therapy unit 2320 compared to when therapywas not administered. Alternatively, the therapy may be administered byother than a therapy unit 2320, e.g., by the patient's oral ingestion ofa medication, or the like. These comparisons are performed by thetherapy evaluation unit 2590 using measures in a database oftime-ordered values, which may be stored in local database unit 2355 ordatabase unit 2350. For example, the measure may be a correct responsetime to a test, optionally weighted by difficulty of the test, andoptionally smoothed as the mean, median, or the like of a series ofvalues. If the correct response time(s) for administrations of the testis/are lower when a therapy is administered than when it is not, thetherapy's efficacy may be quantified, for example, as the percentreduction of the duration and/or severity of the patient's loss ofresponsiveness. Efficacy may also be quantified as the change in thelatency time from medical event detection (as determined by, e.g., aPOMEDA) to loss of function (e.g., the first iteration of the test inwhich the patient responded incorrectly) over the course of a desiredtime interval such as weeks, months, or years.

A therapy evaluation unit 2590 may be desirable for inclusion in amedical device system wherein the medical device system delivers atherapy for a seizure event to the patient. In one embodiment, thetherapy for the seizure event is selected from the group consisting ofelectrical stimulation of a cranial nerve of the patient, thermalmanipulation of the cranial nerve of the patient, electrical stimulationof the brain of the patient, thermal manipulation of the brain of thepatient, delivery of a chemical agent to the patient via thebloodstream, the cerebrospinal fluid or directly to brain tissue,performance of a motor task, performance of a perceptual task,performance of a cognitive task, and two or more thereof.

In one embodiment, the therapy evaluation unit 2590 may be incorporatedinto the medical device 2300 (see, for example, FIG. 25A).

Though not shown, the person of ordinary skill in the art willunderstand a medical device system according to the present disclosuremay comprise any two or all three of a responsiveness parameter unit2388, a medical event characterization unit 2489, and a therapyevaluation unit 2590. For example, the medical device system maycomprise both the medical event characterization unit 2489 and thetherapy evaluation unit 2590, and the therapy evaluation unit 2590 mayincorporate in its therapy evaluation event duration and/or eventseverity values reported by the medical event characterization unit2489.

One or more of the blocks illustrated in the block diagram of the MD2300 in FIGS. 23-25 may comprise hardware units, software units,firmware units, or any combination thereof. Additionally, one or moreblocks illustrated in FIGS. 23-25 may be combined with other blocks,which may represent circuit hardware units, software algorithms, etc.Additionally, any number of the circuitry or software units associatedwith the various blocks illustrated in FIGS. 23-25 may be combined intoa programmable device, such as a field programmable gate array, an ASICdevice, etc.

The medical device system of one embodiment of the present disclosureprovides for software module(s) that are capable of acquiring, storing,and processing various forms of data, such as patient data/parameters(e.g., demographic data, physiological data such as autonomic andneurologic index values, such as heart rate or EKG morphology changes orbreathing rate or pattern changes, among others, disease status(progression, regression, or stabilization), quality of life data,etc.). In one embodiment, the software modules(s) are further capable ofacquiring, storing, and processing therapy parameter data. Therapyparameters may include, but are not limited to, electrical signalparameters that define therapeutic electrical signals delivered by thedevice, medication parameters, and/or any other therapeutic treatmentparameter. In an alternative embodiment, the term “therapy parameters”may refer to electrical signal parameters defining the therapeuticelectrical signals delivered by the IMD. Therapy parameters for atherapeutic electrical signal may also include, but are not limited to,a current amplitude, a pulse width, a pulse shape, a degree of chargebalancing, a frequency, a pulse train pattern, an on-time, an off-time,etc.

In one embodiment, the present disclosure may include coupling of atleast one electrode to each of two or more cranial nerves. (In thiscontext, two or more cranial nerves mean two or more nerves havingdifferent names or numerical designations, and do not refer to the leftand right versions of a particular nerve). In one embodiment, at leastone electrode may be coupled to either or both vagus nerves or a branchof either or both vagus nerves. The term “operatively” coupled mayinclude direct or indirect coupling. Each of the nerves in thisembodiment or others involving two or more cranial nerves may bestimulated according to particular activation modalities that may beindependent between the two nerves.

In one embodiment, the communication unit 2360 is capable, based on thepatient's responsiveness, of instructing an external device to change anoperating state thereof. For example, the external device may be anautomobile or other vehicle which the patient is driving, and the changein the operating state thereof may be stopping, putting the transmissioninto neutral, applying a parking brake, etc., or two or more thereof.For another example, the device may be a power tool, such as a circularsaw, table saw, jigsaw, chain saw, power sander, lawn mower, weedtrimmer, tiller, cultivator, etc., and the change in the operating statethereof may be stopping its motor or disengaging its cutting or grindingparts from the motor or a drive coupled to the motor. For anotherexample, the device may be an oven, stove, toaster, microwave oven, orother kitchen applicants. For an additional example, the device may be afaucet, a drain, or a gate restricting access to a stairwell, balcony,swimming pool, or other location where a non-responsive person would beat risk of bodily harm or death.

Turning now to FIG. 26, a change in autonomic or neurologic indexdetection unit 2365 a is shown. In certain embodiments, autonomic orneurologic index detection unit 2365 a can trigger an administration ofthe test by providing an appropriate instruction to triggering eventindication receiving unit 2365 (FIGS. 23A-25B). The change in autonomicor neurologic index detection unit 2365 a may comprise one or moresignal detection units, such as a cardiovascular signal detection unit2612, a breathing signal detection unit 2614, a brain signal detectionunit 2616, a motor or kinetic signal detection unit 2618, a skin signaldetection unit 2620, a temperature signal detection unit 2621, a spinalsignal detection unit 2623, a cranial or peripheral nerve signaldetection unit 2622, an eye (pupil or eyelid) signal detection unit2624, and/or a blood parameter signal detection unit 2626. Thecardiovascular signal detection unit 2612 is capable of detecting one ormore of various cardiovascular-related signals, including but notlimited to electrocardiogram (ECG) signals, heart rate (HR) signals, andheart rate variability (HRV) signals. The breathing signal detectionunit 2614 is capable of detecting one or more of variousbreathing/respiratory signals of a patient, including, but not limitedto, breath rate (BR) signals, air flow signals, and tidal volumesignals. The breathing/respiratory parameters sensed by the unit 514 mayinclude, but is not limited to, air flow measurements, volumemeasurements, transthoracic inductance, impedance plethysmogrphs,thoracic circumference, and pneumatic respiration, among others. Someembodiments of the unit 2614 may include at least one of a spirometer, anasal thermocoupler measurement device, a strain gauge, a pneumaticrespiration transducer, an impedance measurement device, and/or otherdevices capable of detecting respiratory signals.

The brain signal detection unit 2616 is capable of detecting one or moreof various brain signals, including, but not limited to, EEG signals,field potentials or multiunit activity; fast neuronal oscillations (>100Hz); near DC or DC potentials, event-related potentials, neurotranmitterconcentrations, ionic concentrations, pH, glucose concentrations, freeradicals and/or other brain signals known to those skilled in the art.The body kinetic signal detection unit 2618 may include anaccelerometer, an inclinometer, and/or other kinetic or forcemeasurement devices capable of detecting movement in one or more areasor limbs of the patient's body. The skin signal detection unit 2620 iscapable of detecting one or more of various skin parameters, such asimpedance or other bioelectrical measurements relating to the skin,sweat amount, sweat chemical composition, etc. The cranial nerve signaldetection unit 2622 is capable of detecting one or more of varioussignals relating to cranial nerves, such as amplitude, rate anddirection of action potential traffic, type of fiber (by size andpresence or absence of myelinization) activated, polarity, transmembranevoltage parameter, etc. The temperature signal detection unit 2621 iscapable of detecting one or more of various types of body temperatureparameters, including, but not limited to core temperature changes,organ (e.g., brain) or body part (e.g., facial) temperature, etc. Theunit 2621 may include an infrared sensing device, a chemical-reactionbased temperature sensing device, a direct temperature measurementdevice, etc. The spinal signal detection unit 2623 is capable of sensingone or more of various spinal signals, including, but not limited to,motor neuron signals, sensory pathway signals, autonomic signals, etc.

The eye signal detection unit 2624 is capable of detecting one or moreof various signals relating to the eye, including autonomic functionsincluding, without limitation, pupil width and dilation, eyelid movementand/or phenomena such as mydriasis, miosis, ptosis and/or hippus. Theblood signal detection unit is capable of detecting one or more bloodparameters including, without limitation, oxygen saturation, glucoseconcentration, and/or blood pH.

Each unit 2612-2626 present in the change in autonomic or neurologicindex detection unit 2365 a is capable of communicating detectedsignals, or data generated from the detected signals, to an autonomic orneurologic index data processing unit 2625, which is capable ofdetermining a change in an autonomic or neurologic index, which mayinvolve accessing prior autonomic or neurologic index information storedin, e.g., memory 2317, local database unit 2355, and/or database unit2350.

The autonomic or neurologic index data processing unit 2625 may compriseone or more subunits capable of performing autonomic or neurologic indexquantification, autonomic or neurologic index classification, or both.In particular, autonomic or neurologic index data processing unit 2625may process one or more autonomic or neurologic signals from units2612-2626 according to one or more event detection algorithms to providean appropriate instruction (e.g., a POMEDA or a NOMEDA) to triggeringevent indication receiving unit 2365 (FIGS. 23A-25B) to trigger anadministration of the test.

Turning now to FIG. 27A, a flowchart depiction of a method ofdetermining a responsiveness of a patient is shown, in accordance withone illustrative embodiment of the present disclosure. Monitoring 2710for an indication of a triggering event, such as a signal from autonomicor neurologic index detection unit 2365 a, is performed. Monitoring 2710may be performed at any desirable time scale (from milliseconds toyears), sampling rate (in Hz), and digital precision (in bits), whichmay be relatively rapid or relatively slow depending upon the nature ofthe signal being measured. Rapid sampling may be made for ECoG signals(e.g., about 2 KHz) or ECG signals (200 Hz to 1000 Hz), among others.Much slower sampling rates may be used for other autonomic signals,including rates as slow as once every 1 sec, 5 sec, 10 sec, 15 sec, orlonger, including DC recording. Data collection or sampling may becontinued or interrupted if one or more steps 2740-2788 are performed.Data can also be conditioned according to techniques known in the art,if desired.

After monitoring 2710 is performed, a determination 2720 is made as towhether a triggering event is occurring or has occurred. The triggeringevent may be a medical event (such as a medical event indicated byautonomic or neurologic index detection unit 2365 a) or a non-medicalevent, such as a manual signal from a patient or caregiver, or a signalfrom one or more random timers indicating the need for an administrationof a responsiveness test. If no triggering event occurred, monitoring iscontinued 2730. On the other hand, if a triggering event did occur, atest of responsiveness can be administered 2740. In one embodiment,administration 2740 of the test of responsiveness follows thedescription of test administration set forth above. After administration2740, a decision 2760 is made as to whether a further determinationshould be made based on a test result. The decision parameters may befixed in manufacture of a device or software implementing the method,reprogrammable by a practitioner during ongoing implementation of themethod, and/or automatically adjustable by the device or software duringongoing implementation of the method. In one embodiment, thedetermination 2760 may function such that a “no” decision in step 2760indicates a normal or baseline responsiveness of the patient. In thisembodiment, following a “no” decision, monitoring may be continued 2730.

The factors considered in the determination 2760 may be adjusted toincrease or decrease the specificity, sensitivity, or both of theprocess.

If a further determination is to be made based on the test result, i.e.,upon a “yes” decision in step 2760, one or more determinations 2781-2790may be made. In the depicted embodiment, these determinations 2781-2790(listed in no particular order) include (2781) a time of occurrence of achange in the patient's responsiveness, (2782) a duration of a change inthe patient's responsiveness; (2783) a magnitude of a change in thepatient's responsiveness, (2784) a type (e.g., motor or cognitive) ofchange in the patient's responsiveness, (2785) a determination of eventseverity and/or classification for the patient (e.g., a classificationof a seizure into clinical or subclinical and/or a classification of aclinical seizure into simple partial, complex partial, or generalized);(2786) a formulation of a prognosis for the patient; (2787) anestimation of a risk of injury or death for the patient; (2788) anassessment of efficacy of a therapy for the patient's medical condition;and (2790) a latency from medical event detection to loss of function.Steps 2781-2790 may be executed in parallel (simultaneously), in theorder that maximizes operational efficiency and therapeutic efficacy orin any order as required by the application. If monitoring (step 2710)has been discontinued while any of the other steps (2781-2790) are beingperformed, step 2710 will resume immediately upon termination of steps2781-2790.

The determining steps 2781-2790 may be performed in their entiretybefore returning to monitoring step 2710, but they need not be. In oneembodiment, the “yes” decision in step 2750 instructs an appropriatedevice or software to initiate determining steps 2781-2790, gives thedevice or software information gathered in steps 2720, 2740, and/or 2760to allow the determining steps 2781-2790 to be executed and performcalculations using that information, and, if needed, gives the device orsoftware permission to access a database, such as may be stored in,e.g., memory 2317, local database unit 2355, and/or database unit 2350.Thereafter, the device or software may implement determining steps2781-2790 in parallel or in any desired order with resumed monitoring2710.

Also, it should be noted that not all medical events, and not even allepileptic seizures, are necessarily associated with impaired or abnormalresponsiveness but these (and those associated with impairedresponsiveness) may be associated with distinctive feelings, sensations,emotions, illusions, hallucinations, thoughts, or impulses/behaviors. Inone embodiment, the approaches and methods described herein allow theclassification of epileptic seizures into clinical (subjective orobjective phenomenology is present) or subclinical (neither subjectivenor objective phenomenology is present) seizures, wherein the clinicalseizures may be further classified into simple partial, complex partial,or generalized seizures. The distinction between complex and secondarygeneralized may be made using other seizure severity measures (e.g.,peak heart rate x duration). For simple partial seizures, one or moreautonomic and/or neurologic indices and/or features from each signalthereof may be used to distinguish seizures from non-ictal tachycardia.

FIG. 27B contains many elements like to those of FIG. 27A, which willnot be separately discussed here. In the embodiment depicted in FIG.27B, upon a “yes” decision 2760, and/or a determination of a latency2790, in addition to the determining steps 2781-2790, a decision 2770 ismade to deliver and/or modify therapy. For example, the decision 2770may be to initiate delivery of electrical stimulation to a neuralstructure, such as a cranial nerve; change one or more parametersdefining an electrical signal, such as the pulse width, pulse frequency,on-time/off-time ratio, or other parameters of electrical stimulation toa neural structure, such as a cranial nerve, deliver or change thedosage of a drug administered to the patient; etc.

FIG. 27C contains many elements like to those of FIG. 27A and/or FIG.27B, which will not be separately discussed here. In the embodimentdepicted in FIG. 27C, upon either or both of the “yes” decisions yieldedby decision nodes 2720 and 2760, the process flow may be directed tostep 2775, wherein at least one autonomic or neurologic index value asdescribed above is considered to suggest whether a medical event isoccurring (e.g., whether a POMEDA or a NOMEDA signal is present). Forexample, the autonomic or neurologic index value may be heart rate, anda heart rate value of at least 100 BPM may be taken as suggestive thatan epileptic medical event is occurring. Generally, one or more valuesof one or more indices can be taken as suggestive that a medical eventis occurring. If the autonomic or neurologic index value suggests amedical event is occurring, flow may be returned to the step subsequentto the “yes” decision, e.g., administering 2740 or any one or more ofthe determining steps 2781-2790. If the autonomic or neurologic indexvalue suggests a medical event is not occurring, flow may be directed tothe continue monitoring step 2730.

FIG. 27D depicts in more detail one particular embodiment ofadministering 2740. In the embodiment depicted in FIG. 27D, a test isinitially selected 2741 based on one or more of the patient's baseline,the time of day, week, month, or year, values of one or more autonomicindices, or two or more thereof, among others.

The initially selected test may be modified 2742 in view of prior testresults or based on an ongoing event. “Modified” is used herein to meanthe initially selected test may be made more difficult, less difficult,longer, shorter, replaced with a different cognitive test, or two ormore thereof. For example, modifying may encompass increasing the volumeof an auditory test, switching from a visual to a tactile or auditorytest, or switching from a more complex cognitive test to a simpler test,among others.

The prior test results may be one or more of historical results overdays, weeks, months, or even longer, or the results of previousiterations of the method administered during the same presumptive event.

The person of ordinary skill in the art will understand that variationsin any of the depicted methods may be performed. For example,embodiments shown in FIGS. 27A-27C may be implemented together. For oneexample, the embodiment of FIG. 27C may be modified such that steps2710-2760 are used to override a POMEDA determined from an autonomic orneurologic index value. For another example, the embodiments of FIGS.27A-27C may be implemented at different times as part of the treatmentregimen of one patient. For example, at different times of day, of theweek, of the month, or of the year, the clinician may find itappropriate to perform different methods depicted in FIGS. 27A-27C.

In one embodiment, shown in FIG. 27E, the triggering event is a changein an autonomic or neurologic index, such as those discussed above. Upona “yes” decision in node 2775, flow returns to administering 2740.Thereafter, it is determined at node 2790 whether the patient'sresponsiveness is or is not impaired. If the patient's responsiveness isnot impaired, a determination 2791 is made whether there is anindication of a simple partial seizure. In one embodiment of thedetermination 2791, the subject or an observer is asked if there is/wasa clinical manifestation of a seizure, such as a sensation (typical forthe seizure) or a visible manifestation. If yes, the seizure identifiedby node 2775 is classified 2792 as a simple partial seizure. If no, theseizure identified by node 2775 is classified 2793 as a subclinicalseizure.

If the patient's responsiveness is impaired, a determination 2794 ismade whether a seizure severity value has exceeded a threshold. If yes,the seizure identified by node 2775 is classified 2795 as a generalizedseizure. If no, the seizure identified by node 2775 is classified 2796as a complex partial seizure.

As should be apparent from the foregoing discussion, the various methodsteps may be performed by one or more devices, such as a medical device2300 in concert with an external unit 2370.

Example

A study was conducted at a major university medical center in subjectswith pharmaco-resistant localization-related epilepsies undergoingsurgical evaluation. After signing the consent form, subjects wereenrolled into this study in the order of admission. The surgicalassessment was conducted in accordance with this institution's protocolwhich included discontinuation of anti-seizure drugs or reductions indose.

Inclusion criteria were: 1. Good candidate for invasive epilepsy surgeryevaluation (subjects with at least one seizure/month on two or moreappropriate medications at therapeutic serum concentrations); 2. Normalmotor function; 3. Normal vision with or without correction; and 4. Lowaverage IQ or higher.

Exclusion criteria were: 1. Mental retardation; 2. Status epilepticusduring evaluation prior to collection of an adequate sample of testpresentations and responses; 2. Use of rescue or psychoactive or CNSdepressant drugs prior to collection of an adequate sample of testpresentations and responses; 3. Medical or neurological complicationprior to collection of an adequate sample of test presentations andresponses and 4. Subject voluntary withdrawal prior to collection of anadequate sample of test presentations and responses.

Patient information is shown below in Tables 1-2.

To estimate the latency/time to impairment of complex reaction timeresponses from the time of electrographic onset recorded using depth orsubdural electrodes, this test was administered to each subject undertwo conditions: a) Randomly and b) During seizures (triggered byautomated detection). Complex reaction time tests were chosen in theexpectation they would provide more insight into cognitive status thansimple reaction time tests, while allowing frequent re-testing (withoutprominent training effect), as needed for this task, given the shortaverage duration of seizures and of the study. Testing began no earlierthan 24 hr after electrode implantation to allow for recovery fromanesthesia and immediate postoperative pain/discomfort.

Test Description

Each subject received instructions as to how to take the test and had atraining session that had to be successfully completed prior to thestart of the trial. The complex reaction time (FIG. 7) consisted of theserial and simultaneous presentation of a pair of visual “stimuli” (theletter “A” and a square “□”), displayed full screen simultaneously on a15″ monitor positioned at eye level, at a comfortable distance from thesubject. The position of the letter on either half of the screen (i.e.,left “A □”, or right “□ A”), was randomly chosen for each presentationand the subject was instructed to immediately press, upon appearance ofeach visual stimuli, either the left or right mouse button according tothe side of the screen (left or right) on which the letter A appeared.As soon as the subject pressed either button, or after a maximalpresentation time (1 s) had elapsed, in case of no response, eachstimulus presentation was removed (resulting in a blank screen) untilthe next stimuli. At the end of each presentation, a random timer wasset, the expiration of which would trigger the next presentation. Atotal of 36 stimuli were presented in each testing session. Inter-trialpresentation time intervals were randomly chosen from the set {0.5, 1.0,1.5, 2.0 s.} to minimize adaptation and better assess performance.

Timing of Complex Reaction Time Tests Administration

The Complex Reaction-time tests were triggered only between 08:00-20:00daily, throughout the surgical monitoring period by: a) Seizures [viathe earlier of real-time automated seizure detection (Osorio et al,2002) or event button presses] and b) Randomly. The timer that triggeredrandom complex reaction time tests was set for 6 presentations per day,uniformly distributed throughout the 12 hour test period, with theadditional constraints that no random test could occur within the 15minutes period after a seizure or a randomly triggered test. To minimizefatigue, no more than a total of 30 tests (random plusseizure-triggered) could be administered over any 12 hour period.

Whenever a complex reaction time test was triggered, a sound fileconsisting of a voice saying “Begin Test” was automatically played tosummon the subject to take the test. The subject was instructed to, uponhearing the summon, press one of the mouse buttons to activate the test.The “summons” was repeated every 5 s unless the subject began the test,up to a total of 6 times (30 s), with the sound file volume increasingwith each repetition. If the subject did not initiate the complexreaction time test after 30 s, this information was logged and thesystem would go dormant until the next test.

Seizures were detected and quantified (intensity, duration and extent ofspread) with a validated algorithm (Osorio et al 2002), whose output wasused to trigger the complex reaction time tests; most automateddetections occurred within 5 s of electrographic onset as markedvisually by independent experts (Osorio et al, 2002). The classificationof complex reaction time tests as ictal or random/interictal wasvalidated off-line via expert visual analysis of the ECoG segmentsassociated with each test. Complex reaction time tests triggered byfalse positive detections and randomly-triggered tests that overlappedin time with true seizures not detected by the algorithm (falsenegatives) were reclassified accordingly.

Complex Reaction Time Data Recording and Processing

The following were recorded (with millisecond precision) andlogged/saved to the computer's memory: a) Test condition (random vs.seizure); b) Summon times corresponding to each prompt to the subject tostart the test; c) Latency of responses to summons; d) Stimulipresentation times and side of the screen (left vs. right) where theletter “A” was displayed; and e) Times and sides (left vs. right) of allbutton presses. These data were processed to derive the followingmeasures for each subject: I. Compliance, defined as the fraction ofpresented stimuli within each testing session for which the subjectpressed the button regardless of correctness (Compliance Score=#responses/# presentations). II. Percentage of correct responses=#correct responses/# presentations, where correct responses are definedas those for which the subject pressed only once the button ipsilateralto the side (left or right) of the screen where the letter “A” appeared.Responses were classified as incorrect if: a) The mouse buttoncontralateral to where the letter “A” was displayed on the screen waspressed; b) The right and left mouse buttons were pressed simultaneouslyor sequentially; c) The correct button was pressed more than once perstimulus presentation; or d) No button was pressed; III. Time toimpaired response (TIR): The time (in seconds) elapsed between each testsummon and the last correct response prior to the first test failure asdefined below. The mean, range and standard deviation (SD) of time toimpaired response (TIR) was computed for three different definitions oftest failure, from most to least stringent: A) A correct response butwith latency exceeding the 90th percentile of those for random tests(TIR-A); speed of reaction is in certain situations as important ascorrectness of response; B) Any incorrect response as defined in II.above (TIR-B); C) Three consecutive incorrect responses, regardless oftheir response latencies (TIR-C), a definition that attempts to accountfor the fact that subjects make intermittent errors even during randomtests when they presumably are not cognitively impaired. If no failureoccurred in a test, the interval ends with the time of the correctresponse to the last stimuli. However, since assessment is limited tothe duration (75 sec) of the complex reaction time test, the possibilityof impairment after the test's termination cannot be excluded. Using thetime to last correct response, not to the time to first failure (asdefined above), overestimates time to impaired response (TIR), anapproach deemed preferable/“safer” to underestimating it.

Subjects' data were included in the analyses only if: 1. The ECoGtracings were of sufficiently good quality to allow visual ascertainmentof the presence or absence of seizures; and 2. There were at least twoCRTs taken during random and at least one under seizure conditions.

ECoG Recording Processing and Analysis

ECoG was recorded using commercially available depth (mesial temporalregions) or grid/strip electrodes (cerebral convexities) electrodes(Ad-Tech, Racine, Wis.). These signals were fed into commerciallyavailable systems (Nicolet, Madison, Wis.), filtered (0.5-70 Hz;digitized (240 Hz, 10 bits of precision, 0.59 μV/bit) and furtherprocessed using a validated seizure detection and quantificationalgorithm (Osorio 1998, Osorio 2002) implemented into a custom bedsidesystem (Peters et al., 2001). The detection algorithm quantified maximalseizure intensity (Si), duration (Sd); site(s) of seizure origin andextent of spread (Sc) were determined through visual review of ECoG. Forthis study, seizures were defined as any automated detection thatreached an intensity threshold, T=22, for a minimum duration, D=0.84 s.with or without clinical manifestations. These parameters (T and D) wereselected (Osorio et al, 98) to optimize sensitivity and specificity ofthe detection algorithm.

The relation between location and extent of the primary epileptogeniczone(s) and extent of seizure spread (outside the primary epileptogeniczone) and several complex reaction time performance measures (i.e.percent of correct responses; TIR, etc.) was probed. Seizure onset andspread were classified as follows: Focal: Ictal activity restricted to 2contiguous electrode contacts; Regional: Ictal activity in 3 or morecontiguous or non-contiguous contacts, provided the contacts are in thesame region (i.e. left amygdala, pes and body of hippocampus); Lobar:Ictal activity in two or more regions within the same lobe (i.e., mesialtemporal and neocortical temporal); Intrahemispheric: Ictal activity intwo or more regions (in at least 2 different lobes) within the samehemisphere; Interhemispheric: Ictal activity in one or more regions(i.e. right and left mesial temporal regions) and Diffuse: Ictalactivity in one or more lobes in each hemisphere.

In order to better understand the impact of seizure intensity (Si),duration (Sd) and extent of spread (Sc) on complex reaction timeperformance, the percentiles (p) of these three variables were conflatedinto one: Seizure Severity (SS)=pSi+pSd+pSc/3 (Osorio et al 2005) withone modification compared to the original one: using the classificationdefined above the following arbitrary values were assigned to it:Focal=1; Regional=2; Lobar=4; Intrahemispheric=8 andInterhemispheric=16. A scatter plot of seizure severity vs. percentageof correct response and time to impaired response (TIR) for each subjectwas generated and reviewed to assess the relationship between seizureseverity and time to loss of function.

Data Processing Analyses

The data were analyzed for each as well as for all (pooled) subjects,where appropriate. Compliance, defined as the fraction of complexreaction time tests presented divided by those that were taken, wasanalyzed individually (as opposed to pooling the data from all subjects)since the data was skewed by one subject who was presented with 20random tests and took 5 (25%) vs. 134 seizure tests of which 19 weretaken (14%).

To provide additional insight and test for differences that might not beencompassed in an analysis of mean and SD alone, we analyzed thedistributions of the various measures, comparing differences of randomvs. seizure tests with the Kolmogorov-Smirnov test, a goodness of fitnon-parametric test (Lindgren 1976). For each subject, the nullhypothesis, namely, that the random and seizure tests performance arederived from the same distribution (i.e. they are not significantly(p=<0.05) different) was tested.

Since the deleterious impact of complex or secondarily generalizedseizures on cognitive performance is cumulative, when closely spaced intime, all automated detections in a 15 minute window prior to eachrandom or seizure test were annotated and taken into account in theinterpretation of the complex reaction time test performance.

Results

Twenty subjects (See Table 1 for demographics, type, numbers and sitesof electrode implantations and localization of the epileptogenic zone(s)all of which met the inclusion criteria, were enrolled in this study.The data from 6 subjects (4, 6, 7, 9, 12, 13) were excluded fromanalyses as they did not take the minimum required number ofseizure-triggered tests. In 12/14 subjects electrographic onset precededclinical seizure onset; in subjects 16 & 20 clinical precededelectrographic onset and their data was included in the analyses ascontrol.

A total of 856 tests were administered: 649 (76%) were random withsubjects responding to 520 (80%) and 207 (19%) were seizure-triggered(all true positive detections) with subjects responding to 73 (35%).These differences were primarily due to a few subjects who reported“getting tired” of taking large numbers of tests. The mean and SD of theaverage compliance scores for the 14 subjects included in the analyseswere: Random tests: 0.91+/−0.12 vs. Seizure tests: 0.82+/−0.26,differences that were not statistically significant (paired t-test:p˜0.14). The mean and SD of the average percentage of correct responsesfor the 14 subjects were: Random tests: 85+/−14% vs. Seizure tests:76+/−30%, differences that were not statistically significant (pairedt-test: p˜0.15).

Mean maximal seizure intensity, duration and spread for each subject areshown in Table 3.

The mean, range and SD of time to failure (as defined above) for allsubjects are shown in Table 4. Differences in means between seizure andrandom tests were significant for TIR-A (p˜0.02) and TIR-B (p˜0.04), butnot for TIR-C (p˜0.4).

For 3/14 subjects, the Kolmogorov-Smirnov test identified significantdifferences in certain distributions: In subject 5, TIR-A was longer(p˜0.03) for seizures than for random tests; in subjects 8 & 11, thepercentage of correct responses was higher (p˜0.04) for seizures thanfor random tests; in subject 11, the SD of response times for seizuresis larger (p˜0.04) than for random tests.

The relationship between response delay and correctness of response toinstantaneous seizure intensity (regardless of whether tests weretriggered by seizure detection or by a random trigger; in the lattercase, instantaneous seizure intensity was 0) was analyzed using scatterplots and classified into four groups: 1. As seizure intensityincreased, response latency decreased, but without apparent impact onlikelihood of correctness [Subject 14]; 2. As seizure intensityincreased, response delay appeared unchanged, but with an increase inlikelihood of an incorrect choice [Subjects 5, 16, and 20]; 3. Asseizure intensity increased, response delay increased along with anincrease in likelihood of an incorrect choice [Subjects 10 and 11]; and4. As seizure intensity increased, there was no apparent change ineither response delay or likelihood of an incorrect choice [Subjects 2,17, and 19]. In the remaining five subjects, there was insufficient dataat high intensities to identify any relationship between the variables[Subjects 1, 3, 8, 15, and 18].

Relative Seizure Severity (RSS) showed negative correlations between %correct and TIR-A,B,C with RSS for patients 2 (TIR-A), 3 (TIR-A,B), 4(TIR-A,B,C), 5 (TIR-A,B), 6 (% corr, TIR-A,B,C), 7. % corr, TIR-A,B,C),9 (TIR-A,B), 11 (TIR-A,B), 12 (TIR-A,B), and 13 (TIR-B).

Discussion

This study employed automated seizure detection to trigger a complexreaction time test to estimate the length of time following automatedseizure detection for which a subjects' performance is indistinguishablefrom interictal (non-seizure) periods. Reaction time is the timerequired for perceptual processing, evaluation of a stimulus andenactment of a response. Complex (also known as choice or alternative)reaction time, unlike simple reaction time tests, consists of more thanone stimulus, adding complexity that increases with the logarithm of thestimuli number, thus probing thoroughly and in-depth a subject's abilityto correctly and in a timely manner process and evaluate stimuli andgenerate an adaptive response. The process that takes place between thepresentation of a stimulus and the response may be broken down intothree subprocesses listed in order of occurrence: a) a stimulusregistration time; b) a choice reaction time; and c) a time inconstructing a decision to respond. This and the ability tore-administer it multiple times make complex reaction time testssuitable for assessing the impact of seizures onresponsiveness/awareness.

The period (regardless of duration) after detection of seizure onsetduring which performance assessed with this complex reaction time testwas indistinguishable from that obtained interictally, is referredherein to as Time to impaired response (TIR). It is inferred from theseresults that before impairment, subjects are able to acquire andcorrectly process sensory cues and integrate the elements required togenerate an adaptive (appropriate) and timely response. The Time toImpaired Response obtained in this study, under adverse conditions(postoperatively and in an ICU environment), show that in subjects withseizures of mesial temporal origin (which are the majority in thiscohort), the mean time to impaired response (TIR-A: 56.1 s; TIR-B: 27.1s, and TIR-C: 42.8 s) was adequate for implementation/execution ofcertain behaviors, including but not limited to prevention of falls tothe ground, other injuries, and even possibly disengagement from theoperation of power equipment and of motor vehicles (Green, 2000). Thesefindings justify the issuing of automated warning(s) (in addition totherapy) to decrease the risk of injuries and costs of care (both directand indirect) and enhance the quality of life of subjects with seizuresoriginating from certain brain regions. Due to the proclivity ofseizures originating in the frontal lobe to rapidly evolve into complexor secondarily generalized ones and the susceptibility to dysfunction(even to single epileptiform discharges (Shewmon & Erwin I, II, 1988) ofareas subserving vision, subjects with these epilepsies may not benefitfrom short-term warning.

That administration of the complex reaction time tests may have modifiedthe probability of seizure occurrence, their expression, and severity isworth entertaining in light of two observations: 1. When compared withthe 37 other subjects evaluated for epilepsy surgery during the sametime period who were not enrolled in this study, those participatingrequired significantly longer monitoring [by 2.2 days, 8.9 days forenrollees vs. 6.7 days for those not enrolled (p˜0.04)] to capture 5typical clinical seizures; 2. In one subject (#2) the intensity ofseizures during which tests were administered was significantly lower(p<0.001) than those during which tests were not administered. A smallbody of literature (Efron 1957; Paulson 1963; Kuhlman 1978; Papini et al1984; Pritchard et al, 1985; Fenwick 1991) provides examples of seizureabatement, using sensory or other forms of stimulation, and of theincreased likelihood of seizures with decreased vigilance and cognitiveactivity, suggesting that seizures may be amenable to “cognitive”intervention.

As gleaned from these observations, the systematic study of certainaspects of behavior and cognition during the peri-ictus and ictusilluminated heretofore unknown aspects of the mind-seizure interactions,provided means to decrease the burden of epileptics and of theircaregivers, and expanded the realm of activities safely open toepileptics.

REFERENCES

-   Block A, Fisher R S. Can patients perform volitional motor acts at    the start of a seizure? J Clin Neurophysiol. 1999 March;    16(2):141-5.-   Götz-Trabert K, Hauck C, Wagner K, Fauser S, Schulze-Bonhage A.    Spread of ictal activity in focal epilepsy. Epilepsia. 2008    September; 49(9):1594-601. Epub 2008 Apr. 24.-   Quesney L F. Clinical and EEG features of complex partial seizures    of temporal lobe origin. Epilepsia. 1986; 27 Suppl 2: S27-45. Links-   Zajdel R, Nowak D. Simple and complex reaction time measurement.    Computers in Biology and Medicine 37 (12); 1724-30 2007-   Shewmon D A, Erwin R J. The effect of focal interictal spikes on    perception and reaction time. I. General considerations.    Electroencephalogr Clin Neurophysiol. 1988 April; 69(4):319-37.-   Shewmon D A, Erwin R J. The effect of focal interictal spikes on    perception and reaction time. II. Neuroanatomic specificity.    Electroencephalogr Clin Neurophysiol. 1988 April; 69(4):338-52.-   Stern Y, Mayeux R, Cote L. Reaction time and vigilance in    Parkinson's disease. Possible role of altered norepinephrine    metabolism. Arch Neurol. 1984 October; 41(10):1086-9.-   Arnsten A F, Li B M. Neurobiology of executive functions:    catecholamine influences on prefrontal cortical functions. Biol    Psychiatry. 2005 Jun. 1; 57(11):1377-84.-   Li G Y, Ueki H, Kawashima T, Sugataka K, Muraoka T, Yamada S.    Involvement of the noradrenergic system in performance on a    continuous task requiring effortful attention. Neuropsychobiology.    2004; 50(4):336-40-   Egelman D M, Person C, Montague P R. A computational role for    dopamine delivery in human decision-making. J Cogn Neurosci. 1998    September; 10(5):623-30.-   Berridge C W, Waterhouse B D. The locus coeruleus-noradrenergic    system: modulation of behavioral state and state-dependent cognitive    processes. Brain Res Brain Res Rev. 2003 April; 42(1):33-84.-   Shouse M N, Staba R J, Ko P Y, Saquib S F, Farber P R. Monoamines    and seizures: microdialysis findings in locus ceruleus and amygdala    before and during amygdala kindling. Brain Res. 2001 Feb. 16;    892(1):176-92.-   Hoshino O. Cognitive enhancement mediated through postsynaptic    actions of norepinephrine on ongoing cortical activity. Neural    Comput. 2005 August; 17(8):1739-75.-   Giorgi F S, Blandini F, Cantafora E, Biagioni F, Armentero M T,    Pasquali L, Orzi F, Murri L, Paparelli A, Fornai F. Activation of    brain metabolism and fos during limbic seizures: the role of locus    coeruleus. Neurobiol Dis. 2008 June; 30(3):388-99. Epub 2008 Mar. 6.-   Rammsayer T. Is there a common dopaminergic basis of time perception    and reaction time? Neuropsychobiology 1989; 21:37-42-   Aston-Jones G, Chiang C, Alexinsky T. Discharge of noradrenergic    locus coeruleus neurons in behaving rats and monkeys suggests a role    in vigilance. Prog Brain Res. 1991; 88:501-20.-   Aston-Jones G, Chiang C, Alexinsky T. Discharge of noradrenergic    locus coeruleus neurons in behaving rats and monkeys suggests a role    in vigilance. Prog Brain Res. 1991; 88:501-20.-   Fenwick P. Evocation and inhibition of seizures. Behavioral    treatment. Adv Neurol. 1991; 55:163-83-   Kuhlman W N. EEG feedback training of epileptic patients: clinical    and electroencephalographic analysis. Electroencephalogr Clin    Neurophysiol. 1978 December; 45(6):699-710.-   Pritchard P B, Holmstrom V L, Giacinto J. Self-abatement of complex    partial seizures. Ann Neurol 1985; 18:265-267.-   Papini M, Pasquinelli A, Armellini M, Orlandi D. Alertness and    incidence of seizures in patients with Lennox-Gastaut syndrome.    Epilepsia 1984; 52:161-167.-   Paulson G W. Inhibition of seizures. Dis Nery Syst 1963; 11:657-664.-   Efron R. The conditioned inhibition of uncinate fits. Brain 1957;    80:251-262.-   Lindgren B W. Statistical theory. 3rd ed. New York: Macmillan,    1976:494-5.-   Peters T E, Bhavaraju N C, Frei M G, Osorio I., J Clin Neurophysiol.    2001 November; 18(6):545-9.-   Osorio I, Frei M G, Giftakis J, Peters T, Ingram J, Turnbull M,    Herzog M, Rise M T, Schaffner S, Wennberg R A, Walczak T S, Risinger    M W, Ajmone-Marsan C. Epilepsia. 2002 December; 43(12):1522-35.-   Osorio I, Frei M G, Sunderam S, Giftakis J, Bhavaraju N C, Schaffner    S F, Wilkinson S B. Ann Neurol. 2005 February; 57(2):258-68.-   Osorio I, Frei M G, Wilkinson S B. Epilepsia. 1998 June;    39(6):615-27.-   Green M. How Long Does It Take To Stop?′ Methodological Analysis of    Driver Perception-Brake Times. Transportation Human Factors, 2000;    2:195-216. Begley, C. E., M. Famulari, J. F. Annegers, D. R.    Lairson, T. F. Reynolds, S. Coan, S. Dubinsky, M. E. Newmark, C.    Leibson, E. L. So and W. A. Rocca (2000). “The cost of epilepsy in    the United States: an estimate from population-based clinical and    survey data.” Epilepsia 41(3): 342-51.-   Kwan, P. and M. J. Brodie (2000). “Early identification of    refractory epilepsy.” New England Journal of Medicine 342(5): 314-9.

TABLE 1 Site(s) of Subject Origin # of SZs Spread 01 RMT focal 1 No 02LMT focal 19 Regional 03 RTnC 2 Focal RTnC regional No 05 RMT focal 2Regional 08 LMT focal 111 No LMT regional 8 No LMT focal 2Interhemispheric 10 LMT regional 7 No 11 LMT regional 2 Intrahemispheric14 Interhemispheric 10 No 15 R frontal regional 9 No R frontal regional1 Lobar 16 L frontal focal 1 Diffuse 17 RMT focal 1 Regional RMT focal 1Interhemispheric RMT focal 1 No RMT focal 1 Regional LMT focal 1Interhemispheric RTM focal 1 No 18 LMT focal 4 Regional LMT focal 1 No19 RTM focal 1 No RTM focal 1 Regional 20 RTM Regional 1Interhemispheric L = Left; R = Right; M = Mesial; T = Temporal; nC =Neocortical

TABLE 2 Frequency Subject Years with Monthly Zone(s) PrimaryEpileptogenic No. Age epilepsy GenderEtiology Class Baseline & ApproachElectrode Type(s) 1 32 27 F Cryptogenic CP 10 Rt. Amygdala B.D.; Lat. 230 29 F Cryptogenic CP 4 Lt. Amygdala & Pes Hippocampus B.D.; Lat. 3 3422 M Infection Sec. Gral. 5 Rt. Fronto-Temporal Convexity Grid 4 22 4 MTrauma Sec. Gral. 5 Rt. Hippocampus B.D.; Lat. 5 11 4 M Cryptogenic CP16 Rt. Amygdala B.D.; Lat. 6 30 23 F Congenital CP 10 Rt. Amygdala &Hippocampus B.D.; Lat. 7 42 14 M Trauma Sec. Gral. 7 Rt. FrontalConvexity Grid 8 23 23 F Cryptogenic CP N/A Lt. Hippocampus B.D.; Lat. 935 34 F Trauma Sec. Gral. 4 Lt. Frontal Convexity Grid 10 26 26 MInfection CP 15 Left Amygdala & Hippocampus B.D.; Lat. 11 48 38 MCryptogenic CP 75 Rt Amygdala B.D.; Lat. 12 20 8 M Cryptogenic C P 2 Rt.Posterior Hippocampus B.D.; Lat. 13 28 3 M Cryptogenic CP 45Bi-occipital polar B.D. 14 34 22 F Cryptogenic CP 3 Lt. Hippocampus; Rt.Amygdala B.D.; Lat. 15 32 19 M Trauma Sec. Gral. 3 Rt. Frontal ConvexityGrid 16 22 21 F Cryptogenic Sec. Gral. 2 Rt. Post. Hippocampus; Lt.Post. Hippocampus; bi-Fronto-Polar B.D.; Strips 17 19 11 M CryptogenicCP 3 Lt. Hippocampus; Rt. Amygdala B.D.; Lat. 18 21 17 M Trauma CP 4 Lt.Hippocampus B.D.; Lat. 19 25 16 F Cryptogenic Sec. Gral. N/A Lt.Hippocampus B.D.; Lat. 20 30 11 M Cryptogenic CP 16 Rt. Amygdala &HippocampusB.D.; Lat. CP = Complex Partial; Sec. Gral. = SecondarilyGeneralized; B.D. = Bilateral Depth electrodes; Lat. = Lateral(Electrodes are inserted through the temporal bone)

TABLE 3 Subject Mean Maximal Mean Mean Seizures Intensity Duration (s)Spread 01 17.7 4.0 1.0 02 124.8 28.9 2.0 03 5.5 34.0 1.5 05 306.5 17.12.0 08 94.6 6.4 1.3 10 247.0 22.6 2.0 11 607.1 79.4 8.0 14 128.8 16.716.0 15 165.3 4.9 2.2 16 1005.7 36.2 16.0 17 242.0 9.6 6.3 18 842.6 25.85.6 19 3.6 70.0 1.5 20 340.3 87.6 16.0

TABLE 4 Random Tests Seizure Tests Mean SD Range Mean SD Range (s) (s)(s) (s) (s) (s) TIR-A 22.0 17.3 0.2-83.5 27.1 19.8 0.6-75.0 TIR-B 37.225.0 0.2-92.0 42.8 24.2 0.6-82.2 TIR-C 55.5 24.8  2.0-103.0 56.1 23.90.6-88.7 TIR: Time to impaired response, with failure defined as: A.Either an incorrect response or a slow correct response (with latencyexceeding the 90% tile of random test response latencies); B. Anyincorrect response; C. Three consecutive incorrect responses

All of the methods and apparatuses disclosed and claimed herein may bemade and executed without undue experimentation in light of the presentdisclosure. While the methods and apparatus of this disclosure have beendescribed in terms of particular embodiments, it will be apparent tothose skilled in the art that variations may be applied to the methodsand apparatus and in the steps, or in the sequence of steps, of themethod described herein without departing from the concept, spirit, andscope of the disclosure, as defined by the appended claims. It should beespecially apparent that the principles of the disclosure may be appliedto selected cranial nerves other than, or in addition to, the vagusnerve to achieve particular results in treating patients havingepilepsy, depression, or other medical conditions.

The particular embodiments disclosed above are illustrative only as thedisclosure may be modified and practiced in different but equivalentmanners apparent to those skilled in the art having the benefit of theteachings herein. Furthermore, no limitations are intended to thedetails of construction or design herein shown other than as describedin the claims below. It is, therefore, evident that the particularembodiments disclosed above may be altered or modified and all suchvariations are considered within the scope and spirit of the disclosure.Accordingly, the protection sought herein is as set forth in the claimsbelow.

In one embodiment, a method for determining a degree of responsivenessof a patient having brain state changes includes receiving an indicationof a triggering event; administering to the patient, in response to theindication, a test of responsiveness; and/or determining, based upon aresult of the test, at least one responsiveness parameter selected fromthe group consisting of (i) a time of occurrence of a change in thepatient's responsiveness, (ii) a duration of a change in the patient'sresponsiveness; (iii) a magnitude of a change in the patient'sresponsiveness, (iv) a time interval from the indication of eventoccurrence to a change in the patient's responsiveness, (v) a type ofchange in the patient's responsiveness, (vi) an estimation of a seizureseverity; (vii) a classification of a seizure into clinical orsubclinical; (viii) a classification of a clinical seizure into simplepartial, complex partial, or generalized; (ix) an assessment of efficacyof a therapy for the patient's medical condition; (x) an assessment ofthe state of the disease and formulation of a prognosis for the patient;(xi) an estimation of a risk of injury or death for the patient; and(xii) two or more thereof.

In another example, the triggering event is selected from the groupconsisting of a) an indication from a medical event detection algorithmthat a medical event is occurring or is imminent; b) a manual signal toadminister the responsiveness test to the patient; or c) a command toadminister a responsiveness test to the patient in the absence of anindication from a medical event detection algorithm that a medical eventis occurring or imminent.

In another example, the method may further include detecting a change inan autonomic index of the patient by analyzing at least one set ofsignals received from the patient and selected from the group consistingof cardiovascular signals, respiratory signals, skin signals, pupillarysignals, temperature signals, peristaltic signals, autonomic nerve organglia signals, and two or more thereof. In addition, the method mayfurther include detecting a change in a neurologic index of the patientby analyzing at least one set of signals received from the patient andselected from the group consisting of brain signals, cranial nervesignals, spinal cord signals, peripheral nerve signals, body kinetic,position and force signals, and two or more thereof. In addition, thepatient may suffers from epilepsy, and administering is performed at aplurality of times, wherein at least one of the plurality of times isictal and at least one of the plurality of times is nonictal. Inaddition, the method may further include selecting a first test ofresponsiveness having a first difficulty level, and, based on thepatient's responsiveness according to the first test, selecting andadministering a second test of responsiveness having a second difficultylevel. In addition, the method may further include selecting a firsttest of responsiveness having a first duration, and, based on thepatient's responsiveness according to the first test, selecting andadministering a second test of responsiveness having a second duration.In addition, the test of responsiveness tests may be a patient's reflex,motor, and/or cognitive functions. In addition, the test ofresponsiveness tests is a cognitive function of the patient and thecognitive function may be selected from the group consisting ofattention, verbal, non-verbal and procedural short-term memory, verbal,non-verbal and procedural long-term memory, language fluency andcomprehension, visuo-spatial functions, auditory discrimination, visualdiscrimination, abstract reasoning, calculations, or two or morethereof. In addition, the method may further include delivering atherapy for a seizure event to the patient, wherein the therapy for theseizure event is selected from the group consisting of electricalstimulation of a cranial nerve of the patient, thermal manipulation ofthe cranial nerve of the patient, electrical stimulation of the brain ofthe patient, thermal manipulation of the brain of the patient, deliveryof a chemical agent to the patient via the bloodstream, cerebrospinalfluid or directly into the brain, magnetic stimulation of a cranialnerve, magnetic stimulation of the brain a motor task, a perceptualtask, a cognitive task, and two or more thereof. In addition, the methodmay further include based on the patient's responsiveness, instructingan external device to change an operating state thereof.

In another embodiment, a computer readable program storage unit encodedwith instructions that, when executed by a computer, perform a methodfor determining a responsiveness of a patient having brain state changesincluding receiving an indication of a triggering event; administeringto the patient, in response to the indication, a test of responsiveness;and/or determining, based upon a result of the test, at least oneresponsiveness parameter selected from the group consisting of (i) atime of occurrence of a change in the patient's responsiveness, (ii) aduration of a change in the patient's responsiveness; (iii) a magnitudeof a change in the patient's responsiveness, (iv) a time interval fromthe indication of event occurrence to a change in the patient'sresponsiveness, (v) a type of change in the patient's responsiveness,(vi) an estimation of a seizure severity; (vii) a classification of aseizure into clinical or subclinical; (viii) a classification of aclinical seizure into simple partial, complex partial, or generalized;(ix) an assessment of efficacy of a therapy for the patient's medicalcondition; (x) an assessment of the state of the disease and formulationof a prognosis for the patient; (xi) an estimation of a risk of injuryor death for the patient; and (xii) two or more thereof.

In addition, the triggering event is selected from the group consistingof a) an indication from a medical event detection algorithm that amedical event is occurring or is imminent; b) a manual signal toadminister the responsiveness test to the patient; and/or c) a commandto administer a responsiveness test to the patient in the absence of anindication from a medical event detection algorithm that a medical eventis occurring or imminent. In addition, the method may further includedetecting a change in an autonomic index of the patient by analyzing atleast one set of signals received from the patient and selected from thegroup consisting of cardiovascular signals, respiratory signals, skinsignals, pupillary signals, temperature signals, peristaltic signals,autonomic nerve or ganglia signals, and two or more thereof. Inaddition, the method may further include detecting a change in aneurologic index of the patient by analyzing at least one set of signalsreceived from the patient and selected from the group consisting ofbrain signals, cranial nerve signals, spinal cord signals, peripheralnerve signals, body kinetic, position and force signals, and two or morethereof. In addition, the patient suffers from epilepsy, andadministering is performed at a plurality of times, wherein at least atleast one of the plurality of times is ictal and at least one of theplurality of times is nonictal. In addition, the method may includeselecting a first test of responsiveness having a first difficultylevel, and, based on the patient's responsiveness according to the firsttest, selecting and/or administering a second test of responsivenesshaving a second difficulty level. In addition, the method may includeselecting a first test of responsiveness having a first duration, and,based on the patient's responsiveness according to the first test,selecting and/or administering a second test of responsiveness having asecond duration. In addition, the test of responsiveness tests at leastone of the patient's reflex, motor, and/or cognitive functions. Inaddition, the test of responsiveness tests a cognitive function of thepatient, wherein the cognitive function is selected from the groupconsisting of attention, verbal, non-verbal and procedural short-termmemory, verbal, non-verbal and procedural long-term memory, languagefluency and comprehension, visuo-spatial functions, auditorydiscrimination, visual discrimination, abstract reasoning, calculations,or two or more thereof. In addition, the method may include delivering atherapy for a seizure event to the patient, wherein the therapy for theseizure event is selected from the group consisting of electricalstimulation of a cranial nerve of the patient, thermal manipulation ofthe cranial nerve of the patient, electrical stimulation of the brain ofthe patient, thermal manipulation of the brain of the patient, deliveryof a chemical agent to the patient via the bloodstream, cerebrospinalfluid or directly into the brain, magnetic stimulation of a cranialnerve, magnetic stimulation of the brain a motor task, a perceptualtask, a cognitive task, and two or more thereof.

In another embodiment, a medical device system for determining aresponsiveness of a patient having brain state changes may include areceiving unit adapted to receive an indication of a triggering event; aresponsiveness testing unit adapted to administer a test ofresponsiveness to a patient in response to the indication; and/or adetermination unit adapted to receive a result of the test and to makeat least one determination selected from the group consisting of (i) atime of occurrence of a change in the patient's responsiveness, (ii) aduration of a change in the patient's responsiveness; (iii) a magnitudeof a change in the patient's responsiveness, (iv) a time interval fromthe indication of event occurrence to a change in the patient'sresponsiveness, (v) a type of change in the patient's responsiveness,(vi) an estimation of a seizure severity; (vii) a classification of aseizure into clinical or subclinical; (viii) a classification of aclinical seizure into simple partial, complex partial, or generalized;(ix) an assessment of efficacy of a therapy for the patient's medicalcondition; (x) an assessment of the state of the disease and formulationof a prognosis for the patient; (xi) an estimation of a risk of injuryor death for the patient; and (xii) two or more thereof.

In addition, the medical device system may include a storage unitadapted to store at least one of the test result or the determination;an autonomic or neurologic index change detection unit adapted to detecta change in an autonomic or neurologic index of the patient; a medicalevent therapy unit adapted to deliver a therapy for a medical event tothe patient; and/or a responsiveness test selection unit adapted toselect at least one of a plurality of tests of responsiveness andinstruct the responsiveness testing unit to administer the selectedtest.

In addition, a method for determining a degree of responsiveness of apatient having brain state changes may include receiving an indicationof a triggering event; administering to the patient, in response to theindication, a test of responsiveness; and/or determining, based upon aresult of the test, at least one responsiveness parameter selected fromthe group consisting of (i) a time of occurrence of a change in thepatient's responsiveness, (ii) a duration of a change in the patient'sresponsiveness; (iii) a magnitude of a change in the patient'sresponsiveness, (iv) a time interval from the indication of eventoccurrence to a change in the patient's responsiveness, (v) a type ofchange in the patient's responsiveness, (vi) an estimation of a seizureseverity; (vii) a classification of a seizure into clinical orsubclinical; (viii) a classification of a clinical seizure into simplepartial, complex partial, or generalized; (ix) an assessment of efficacyof a therapy for the patient's medical condition; (x) an assessment ofthe state of the disease and formulation of a prognosis for the patient;(xi) an estimation of a risk of injury or death for the patient; and(xii) two or more thereof.

In addition, a computer readable program storage unit encoded withinstructions that, when executed by a computer, perform a method fordetermining a degree of responsiveness of a patient having brain statechanges may include receiving an indication of a triggering event;

administering to the patient, in response to the indication, a test ofresponsiveness; and/or determining, based upon a result of the test, atleast one responsiveness parameter selected from the group consisting of(i) a time of occurrence of a change in the patient's responsiveness,(ii) a duration of a change in the patient's responsiveness; (iii) amagnitude of a change in the patient's responsiveness, (iv) a timeinterval from the indication of event occurrence to a change in thepatient's responsiveness, (v) a type of change in the patient'sresponsiveness, (vi) an estimation of a seizure severity; (vii) aclassification of a seizure into clinical or subclinical; (viii) aclassification of a clinical seizure into simple partial, complexpartial, or generalized; (ix) an assessment of efficacy of a therapy forthe patient's medical condition; (x) an assessment of the state of thedisease and formulation of a prognosis for the patient; (xi) anestimation of a risk of injury or death for the patient; and (xii) twoor more thereof.

In addition, a method of determining a responsiveness of a patienthaving brain state changes, comprising receiving an indication of atriggering event; administering to the patient, in response to theindication, a test of responsiveness; determining, based upon a resultof the test, at least one responsiveness parameter selected from thegroup consisting of (i) a time of occurrence of a change in thepatient's responsiveness, (ii) a duration of a change in the patient'sresponsiveness; (iii) a magnitude of a change in the patient'sresponsiveness, (iv) a time interval from the indication of eventoccurrence to a change in the patient's responsiveness, (v) a type ofchange in the patient's responsiveness, (vi) an estimation of a seizureseverity; (vii) a classification of a seizure into clinical orsubclinical; (viii) a classification of a clinical seizure into simplepartial, complex partial, or generalized; (ix) an assessment of efficacyof a therapy for the patient's medical condition; (x) an assessment ofthe state of the disease and formulation of a prognosis for the patient;(xi) an estimation of a risk of injury or death for the patient; and(xii) two or more thereof. A medical device system capable ofimplementing the method.

What is claimed:
 1. A method of treating a medical condition in apatient using an implantable medical device, the implantable medicaldevice including a first electrode coupled to a first cranial nervestructure and a second electrode coupled to a second cranial nervestructure, where the first cranial nerve structure is a left portion ofa cranial nerve and the second cranial nerve structure is a rightportion of the cranial nerve, the method comprising: providing a firstelectrical signal to the first cranial nerve structure of the patientusing a first polarity configuration, the first electrical signal isconfigured to induce action potentials, wherein a charge accumulates asa result of the first electrical signal; switching from the firstpolarity configuration to a second polarity configuration upontermination of the first electrical signal; providing a secondelectrical signal to the second cranial nerve structure in the secondpolarity configuration, the second electrical signal is configured toinduce action potentials in the second cranial nerve structure where atleast a portion of the second electrical signal comprises theaccumulated charge from the first electrical signal; administering tothe patient a responsiveness test and comparing a result of theresponsiveness test to a baseline responsiveness test; and initiating asecond therapy or issuing a warning based on the comparison of theresult of the responsiveness test to the baseline responsiveness test.2. The method of claim 1, wherein one or more processors are configuredto increase a sympathetic tone to increase the heart rate of the patientvia at least one of the second therapy and a third therapy.
 3. Themethod of claim 1, wherein one or more processors are configured todecrease a parasympathetic tone to increase the heart rate of thepatient via at least one of the second therapy and a third therapy. 4.The method of claim 1, wherein one or more processors are configured todecrease a sympathetic tone to decrease the heart rate of the patientvia at least one of the second therapy and a third therapy.
 5. Themethod of claim 1, wherein one or more processors are configured toincrease a parasympathetic tone to decrease the heart rate of thepatient via at least one of the second therapy and a third therapy. 6.The method of claim 1, further comprising a seizure detection unitcapable of analyzing the at least one body data stream to determine anepileptic seizure status.
 7. The method of claim 1, further comprising:collecting body data of the patient by at least one of anelectrocardiography (EKG) device, an accelerometer, an inclinometer, apupillometer, a face or body temperature monitor, a skin resistancemonitor, a sound sensor, or a pressure sensor; determining an autonomicindex; and detecting a change in the autonomic index of the patient byanalyzing at least one set of signals received from the patient andselected from a signal group consisting of cardiovascular signals,respiratory signals, skin signals, pupillary signals, temperaturesignals, peristaltic signals, autonomic nerve or ganglia signals, andtwo or more thereof.
 8. The method of claim 1, further comprising:collecting body data of the patient by at least one of anelectrocardiography (EKG) device, an accelerometer, an inclinometer, apupillometer, a face or body temperature monitor, a skin resistancemonitor, a sound sensor, or a pressure sensor; determining an autonomicindex; and detecting a change in the neurologic index of the patient byanalyzing at least one set of signals received from the patient andselected from a signal group consisting of brain signals, cranial nervesignals, spinal cord signals, peripheral nerve signals, body kinetic,position and force signals, and two or more thereof.
 9. The method ofclaim 1, wherein the responsiveness test includes a first test ofresponsiveness having a first difficulty level, and, based on thepatient's responsiveness according to the first test, selecting andadministering a second test of responsiveness having a second difficultylevel.
 10. The method of claim 1, wherein the responsiveness testincludes a first test of responsiveness having a first duration, and,based on the patient's responsiveness according to the first test,selecting and administering a second test of responsiveness having asecond duration.
 11. The method of claim 1, wherein the test ofresponsiveness tests a cognitive function of the patient, wherein thecognitive function is selected from a cognitive function groupconsisting of: an attention; a reaction time; a verbal, a non-verbal anda procedural short-term memory; a verbal, a non-verbal and a procedurallong-term memory; a language fluency and comprehension; a visuo-spatialfunctions; an auditory discrimination; a visual discrimination; anabstract reasoning; calculations; or two or more thereof.
 12. The methodof claim 1, further comprising, based on the patient's responsiveness,instructing an external device to change an operating state thereof. 13.The method of claim 1, wherein the test of responsiveness furthercomprises a test to determine a patient's capacity to perform thepurposeful response.
 14. The method of claim 1, wherein the test ofresponsiveness includes testing at least one of a reflex, a motor, orcognitive functions of the patient.
 15. The method of claim 1, whereinat least one responsiveness parameter includes at least one of: (i) aduration of a change in the patient's responsiveness; (ii) a magnitudeof a change in the patient's responsiveness, (iii) a time interval fromthe indication of the detection of the epileptic seizure to a change inthe patient's responsiveness, (iv) a type of change in the patient'sresponsiveness, (v) an estimation of a seizure severity; (vi) aclassification of a seizure into clinical or subclinical; (vii) aclassification of a clinical seizure into simple partial, complexpartial, or generalized; (viii) an assessment of efficacy of a therapyfor the patient's medical condition; (ix) an assessment of the state ofthe disease and formulation of a prognosis for the patient; (x) anestimation of a risk of injury or death for the patient; and (xi) two ormore thereof.
 16. A method for determining a degree of responsiveness ofa patient suffering from epilepsy and for classification of seizures,comprising: collecting body data of the patient by anelectrocardiography device; monitoring the body data for occurrences ofseizures and issuing a positive output of a seizure detection based on adetection of at least one of an imminent or an on-going epilepticseizure and issuing a negative output of the seizure detection based ona lack of the detection of the at least one of the imminent or theon-going epileptic seizure; in response to one or more negative outputsof seizure detections, determining a non-seizure degree ofresponsiveness, wherein a non-seizure degree of responsiveness testingcomprises at least one of a test of motor function, a test of alertness,a test of attentiveness, a test of short-term memory, a test oflong-term memory, a test of language comprehension or fluency, a test ofvisuo-spatial functions or a test of reflexive functions; in response toone or more positive outputs of seizure detections, delivering a therapyvia a therapy unit and determining a seizure degree of responsiveness,wherein a seizure degree of responsiveness testing comprises at leastone of the test of motor function, the test of alertness, the test ofattentiveness, the test of short-term memory, the test of long-termmemory, the test of language comprehension or fluency, the test ofvisuo-spatial functions or the test of reflexive functions; comparingvia a responsiveness parameter unit, the seizure degree ofresponsiveness with the non-seizure degree of responsiveness; confirmingan epileptic seizure based on the determination that the seizure degreeof responsiveness of the patient is impaired compared to the non-seizuredegree of responsiveness; classifying the epileptic seizure as clinicalseizure, based on the determination that the seizure degree ofresponsiveness is impaired; and in response to the occurrence of aclinical seizure, issuing a warning and logging to memory at least oneof a time of an occurrence of a change in the patient's responsiveness,a duration of a change in the patient's responsiveness, a magnitude of achange in the patient's responsiveness, a time interval from anindication of event occurrence to a change in the patient'sresponsiveness, a type of change in the patient's responsiveness and anestimate of a seizure severity.
 17. The method of claim 16, wherein theepileptic seizure is classified as a subclinical or as a simple partial,if the degree of responsiveness in response to the indication of thedetection is not impaired compared to the degree of responsivenessduring non-seizure periods.
 18. The method of claim 16, wherein theclinical seizure is further classified into partial simple, partialcomplex or generalized, based on the duration of the impairment in thepatient's responsiveness, the magnitude of the impairment in thepatient's responsiveness, a time interval from the indication of thepositive output of the seizure detection to the occurrence to ofimpairment in the patient's responsiveness, the type of change in thepatient's responsiveness and the estimate of a seizure severity.
 19. Themethod of claim 16, wherein the therapy delivered is determined to benon-efficacious if, the epileptic seizure is classified as the clinicalseizure and as efficacious if the epileptic seizure is classified as asubclinical seizure or as a simple partial seizure.
 20. A non-transitorycomputer readable program storage unit having embodied thereoninstructions that, when executed by a computer, perform a method fordetermining a responsiveness of a patient suffering from epilepsy, themethod comprising: generating via one or more processors an indicationfrom a medical event detection algorithm, based upon one or more bodyparameters of the patient, that a medical event relevant to a patient'scondition is occurring based on changes in a heart, the indicationcorresponding to a positive output or affirmative output of the medicalevent detection algorithm; presenting or delivering a cognitive test ofresponsiveness to the patient triggered by the positive output or theaffirmative output from the medical event detection algorithm, andlogging into a memory a first response of the patient to the cognitivetest of responsiveness; presenting or delivering to the patient anidentical cognitive test of responsiveness to that presented with thepositive output or the affirmative output from the medical eventdetection algorithm but at different times triggered randomly,periodically or pseudo-randomly during a daytime or a night timetriggered by a negative output of the medical event detection algorithmand logging into the memory a second response of the patient to theidentical cognitive test of responsiveness; based on a comparison of thefirst response and the second response where the comparison is loggedinto the memory, determining at least of one of: a time to impairment ofcognition or responsiveness measured from the time of the positiveoutput or the affirmative output from the medical event detectionalgorithm is issued; whether or not the patient provides any responsesand a response time occurrence; a number of incorrect responses; or atime required for the patient to regain cognition or responsiveness to alevel or degree similar to that determined from the negative output ofthe medical event detection algorithm; and issuing a warning.